Permanently charged sodium and calcium channel blockers as anti- inflammatory agents

ABSTRACT

The invention provides compounds, compositions, methods, and kits for the treatment of neurogenic inflammation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit of U.S. Provisional Application No.61/224,512, filed Jul. 10, 2009, which is hereby incorporated byreference.

FIELD OF THE INVENTION

The invention provides compounds, methods and kits for the treatment ofneurogenic inflammation.

BACKGROUND OF THE INVENTION

The invention features methods and kits for the treatment of neurogenicinflammation by targeting nociceptors with drugs of low molecularweight, while minimizing effects on non-pain-sensing neurons or othertypes of cells. According to the method of the invention, small,hydrophilic drug molecules gain access to the intracellular compartmentof pain-sensing neurons via entry through receptor/channels that arepresent in pain-sensing neurons but to a lesser extent or not at all inother types of neurons or in other types of tissue. Neurogenicinflammation is a mode of inflammation mediated by the efferent (motor)functions of sensory neurons, in which pro-inflammatory mediatormolecules released in the periphery by pain-sensing neurons(nociceptors) both activate a variety of inflammatory pathways and alsoact on the vascular system to alter blood flow and capillarypermeability.

Neurogenic inflammation contributes to the peripheral inflammationelicited by tissue injury, autoimmune disease, infection, exposure toirritants in a variety of tissues, and is thought to play an importantrole in the pathogenesis of numerous disorders (e.g. migraine,arthritis, rhinitis, gastritis, colitis, cystitis, and sunburn).

One way to reduce neurogenic inflammation is to block excitability innociceptors, thereby preventing the activation of nociceptor peripheralterminals and the release of pro-inflammatory chemicals. Localanesthetics such as lidocaine and articaine act by inhibiting voltagegated ion channels in neurons. Local anesthetics are relativelyhydrophobic molecules that gain access to their blocking site on thesodium channel by diffusing into or through the cell membrane. However,these anesthetics block sodium or calcium channels and thereby theexcitability of all neurons, not just pain-sensing neurons. Thus,administration of local anesthetics produces unwanted or deleteriouseffects such as general numbness from block of low threshold pressureand touch receptors, motor deficits from block of motor axons and othercomplications from block of autonomic fibers. Local anesthetics also acton sodium channels on smooth muscle in the cardiovascular andrespiratory systems producing deleterious effects.

Accordingly, there is a need for an approach to reducing neurogenicinflammation that selectively targets nociceptors.

SUMMARY OF THE INVENTION

In a first aspect, the invention features a method for treatingneurogenic inflammation in a patient, such as a human, by administeringa therapeutically effective amount of a compound that is capable ofentering a nociceptor through a channel-forming receptor present in thenociceptor when the receptor is activated and inhibiting a voltage-gatedion channel present in the nociceptor, wherein the compound does notsubstantially inhibit said channel when applied to the extracellularface of the channel and when the receptor is not activated. In certainembodiments, the compound is an inhibitor of voltage-gated sodiumchannels. Exemplary inhibitors of this class are QX-314,N-methyl-procaine, QX-222, N-octyl-guanidine, 9-aminoacridine andpancuronium. In other embodiments, the compound is a quarternary aminederivative or other charged derivative of a compound selected fromriluzole, mexilitine, phenyloin, carbamazepine, procaine, articaine,bupivicaine, mepivicaine, tocainide, prilocaine, diisopyramide,bencyclane, quinidine, bretylium, lifarizine, lamotrigine, flunarizine,and fluspirilene. In other embodiments, the compound is an inhibitor ofcalcium channels. Inhibitors of this class include D-890, CERM 11888,N-methyl-verapamil, N-methylgallopamil, N-methyl-devapamil,dodecyltrimethylammonium, and terpene compounds (e.g., sesquiterpenes),as well as charged derivatives (e.g., a quarternary amine derivative ora guanylated derivative) of verapamil, gallopamil, devapamil, diltiazem,fendiline, mibefradil, or farnesyl amine. Still other exemplaryinhibitors of calcium channels can be described by Formulas XI-XIV) andin Tables 1, 2, and 3. In further embodiments, the ion channel inhibitoris a charged derivative (e.g., a quarternary amine derivative or aguanylated derivative) of any of compounds (1)-(563). Exemplaryderivatives are described herein.

The channel-forming receptor can be activated prior to administering thecompound by administration of a second compound that opens the channel.Alternatively, the channel-forming receptor can be activated byendogenous compounds present in the patient.

The invention also features a kit that includes a composition fortreating neurogenic inflammation in a patient and instructions for theadministration of the composition to a patient to treat neurogenicinflammation. The composition includes a compound that is capable ofentering a nociceptor through a channel-forming receptor present in thenociceptor when the receptor is activated and inhibiting a voltage-gatedion channel present in the nociceptor, wherein the compound does notsubstantially inhibit said channel when applied to the extracellularface of the channel and when the receptor is not activated. In certainembodiments, the compound is an inhibitor of voltage-gated sodiumchannels or calcium channels, such as those described herein. In someembodiments, the compound is QX-314, N-methyl-procaine, QX-222,N-octyl-guanidine, 9-aminoacridine, pancuronium, or another lowmolecular weight, charged molecule that inhibits voltage-gated sodiumchannels when present inside of said nociceptor. In other embodiments,the compound is D-890, CERM 11888, N-methyl-verapamil,N-methylgallopamil, N-methyl-devapamil, and dodecyltrimethylammonium; aquarternary amine derivative, of verapamil, gallopamil, devapamil,diltiazem, fendiline, mibefradil, or farnesyl amine; a compoundaccording to any of Formulas (XI), (XII), (XIII-A), (XIII-B), (XIII-C),and (XIV); or a quarternary amine derivative or other charged derivativeof any of compounds (1)-(563).

Any of the compositions, methods, and kits of the invention mayoptionally feature a second compound that activates the channel-formingreceptor. In one embodiment, the second compound activates achannel-forming receptor selected from TRPV1, P2X(2/3), TRPA1, andTRPM8.

Activators of TRPV1 receptors include but are not limited to capsaicin,eugenol, camphor, clotrimazole, arvanil (N-arachidonoylvanillamine),anandamide, 2-aminoethoxydiphenyl borate (2APB), AM404, resiniferatoxin,phorbol 12-phenylacetate 13-acetate 20-homovanillate (PPAHV), olvanil(NE 19550), OLDA (N-oleoyldopamine), N-arachidonyldopamine (NADA),6′-iodoresiniferatoxin (6′-IRTX), C18 N-acylethanolamines, lipoxygenasederivatives such as 12-hydroperoxyeicosatetraenoic acid, inhibitorcysteine knot (ICK) peptides (vanillotoxins), piperine, MSK195(N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-2-[4-(2-aminoethoxy)-3-methoxyphenyl]acetamide),JYL79(N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-N′-(4-hydroxy-3-methoxybenzyl)thiourea),hydroxy-alpha-sanshool, 2-aminoethoxydiphenyl borate, 10-shogaol,oleylgingerol, oleylshogaol, SU200(N-(4-tert-butylbenzyl)-N′-(4-hydroxy-3-methoxybenzypthiourea),amylocaine, articaine, benzocaine, bupivacaine, carbocaine, carticaine,chloroprocaine, cyclomethycaine, dibucaine (cinchocaine), dimethocaine(larocaine), etidocaine, hexylcaine, levobupivacaine, lidocaine,mepivacaine, meprylcaine (oracaine), metabutoxycaine, piperocaine,prilocaine, procaine (novacaine), proparacaine, propoxycaine, risocaine,ropivacaine, tetracaine (amethocaine), and trimecaine. Other activatorsof TRPV1 receptors are described in O'Dell et al., Bioorg Med Chem.(2007) 15:6164-6149, and Sexton et al., FASEB J (2007) 21:2695-2703.Still other TRPV1 activators include black pepper compounds (e.g.,Okumura et al., Biosci Biotechnol Biochem. 74(5):1068-72 (2010) andRiera et al., Br J Pharmacol. 57(8):1398-409 (2009)), terpenoids(Iwasaki et al., Life Sci. 85(1-2)60-69 (2009)), nickel (Luebbert etal., Pflugers Arch. 459(5):737-50 (2010)), SA13353([1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea]; see,e.g., Tsuji et al., Eur J Pharmacol. 627(1-3):332-9 (2010)), oxidizedlinoleic metabolites (Patwardhan et al., Proc Natl Acad Sci USA.106(44):18820-4 (2009)), diallyl sulfides (Koizumi et al., BiochemBiophys Res Commun. 382(3):545-8 (2009)), and alkylamides derived fromsanshool (Menozzi-Smarrito et al., J Agric Food Chem. 57(5):1982-9(2009)).

Still other activators of TRPV1 receptors include capsaicinoids andcapsaicinoid analogs as described herein (e.g., vanilloids (e.g.,N-vanillyl-alkanedienamides, N-vanillyl-alkanedienyls, andN-vanillyl-cis-monounsaturated alkenamides), capsiate, dihydrocapsiate,nordihydrocapsiate and other capsinoids, capsiconiate,dihydrocapsiconiate and other coniferyl esters, capsiconinoid,resiniferatoxin, tinyatoxin, civamide, N-phenylmethylalkenamidecapsaicin derivatives, olvanil,N-[(4-(2-aminoethoxy)-3-methoxyphenyl)methyl]-9Z-octa-decanamide,N-oleyl-homovanillamide, triprenyl phenols (e.g., scutigeral),gingerols, piperines, shogaols, guaiacol, eugenol, zingerone, nuvanil,NE-19550, NE-21610, and NE-28345). Additional capsaicinoids, theirstructures, and methods of their manufacture are described in U.S. Pat.Nos. 7,446,226 and 7,429,673, which are hereby incorporated byreference.

Activators of TRPA1 receptors include but are not limited tocinnamaldehyde, allyl-isothiocynanate, diallyl disulfide, icilin,cinnamon oil, wintergreen oil, clove oil, acrolein,hydroxy-alpha-sanshool, 2-aminoethoxydiphenyl borate, 4-hydroxynonenal,methyl p-hydroxybenzoate, mustard oil, 3′-carbamoylbiphenyl-3-ylcyclohexylcarbamate (URB597), amylocaine, articaine, benzocaine,bupivacaine, carbocaine, carticaine, chloroprocaine, cyclomethycaine,dibucaine (cinchocaine), dimethocaine (larocaine), etidocaine,hexylcaine, levobupivacaine, lidocaine, mepivacaine, meprylcaine(oracaine), metabutoxycaine, piperocaine, prilocaine, procaine(novacaine), proparacaine, propoxycaine, risocaine, ropivacaine,tetracaine (amethocaine), and trimecaine. Other activators of TRPA1receptors are described in Taylor-Clark et al., Mol Pharmacol (2007)PMID: 18000030; Macpherson et al., Nature (2007) 445:541-545; and Hillet al., J. Biol. Chem. (2007) 282:7145-7153. Still other TRPA1activators include: fenamate NSAIDS (Hu et al., Pflugers Arch.459(4):579-92 (2010)), congeners of AP18 (Defalco et al, Bioorg Med ChemLett. 20(1):276-9 (2010)), tear gasses CN, CR, and CS (Brône et al.,Toxicol Appl Pharmacol. 231(2):150-6 (2008)), nicotine (Talavera et al,Nat Neurosci. 12(10):1293-9 (2009)), Sichuan and Melegueta peppers(Riera et al., Br J Pharmacol. 157(8):1398-409 (2009)), diallyl sulfidesnifedipine, nimodipine, nicardipine, and nitrendipine, L-type calciumchannel agaonist BayK8644 (Fajardo et al., Channels (Austin) 2(6):429-38(2008)), and isovelleral and polygodial (Escalera et al., J. Biol. Chem.283(35):24136-44 (2008)).

Activators of P2X receptors include but are not limited to ATP,2-methylthio-ATP, 2′ and 3′-O-(4-benzoylbenzoyl)-ATP, andATP5′-O-(3-thiotriphosphate).

Activators of TRPM8 receptors include but are not limited to menthol,icilin, eucalyptol, linalool, geraniol, and hydroxycitronellal.

In another aspect, the invention features compounds according to Formula(XI),

where each R^(11A), R^(11B), and R^(11C) is selected, independently,from H or C₁₋₄ alkyl, and where 0, 1, 2, or 3 of the dashed bondsrepresents a carbon-carbon double bond (i.e., compounds of Formula (XI)can include 0, 1, 2, or 3 double bonds), provided that when 2 or 3carbon-carbon double bonds are present, the double bonds are notadjacent to one another. In some embodiments, compounds of Formula (XI)can be represented by the following formula (XI-A),

where each R^(11A), R^(11B), R^(11C), and X is according to Formula(XI), and where each dashed bond represents an optional carbon-carbondouble bond, or by formula (XI-B),

where each R^(11A), R^(11B), R^(11C), and X is according to Formula(XI). In some embodiments, the compound of Formula (XI) is

In another aspect, the invention features compounds according to Formula(XII),

wherein

each of R^(12A), R^(12B), R^(12C), and R^(12D) is, independently,selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl,C₇₋₁₄ alkaryl, C₃₋₁₀ alkcycloalkyl, and C₃₋₁₀ alkheterocyclyl; orR^(12A) and R^(12B) together complete a heterocyclic ring having atleast one nitrogen atom; n is an integer between 1-5; each of R^(12E)and R^(12F) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₇₋₁₄ alkaryl, C₃₋₁₀alkcycloalkyl, or C₃₋₁₀ alkheterocyclyl; and X is any pharmaceuticallyacceptable anion. In some embodiments, the compound has the followingstructure,

In another aspect, the invention features a compound having a structureaccording to one of the following formulas:

where each R^(13A)-R^(13J) and R^(13O)-R^(13T) is selected,independently, from H, halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₂₋₄ heteroalkyl, C₇₋₁₄ alkaryl, C₃₋₁₀ alkcycloalkyl, and C₃₋₁₀alkheterocyclyl, OR^(13AA), NR^(13AB)R^(13AC), NR^(13AD)C(O)R^(13AE),S(O)R^(13AF), SO₂R^(13AG)R^(13AH), SO₂NR^(13AI)R^(13AJ), SO₃R^(13AK),CO₂R^(13AL), C(O)R^(13AM), and C(O)NR^(13AN)R^(13AO); each ofR^(13AA)-R^(13AO) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; each R^(13K), R^(13L),R^(13M), and R^(13N) is, independently, H or C₁₋₄ alkyl, or R^(13K) (andR^(13L), or R^(13M) and R^(13N), combine to form C═O, or R^(13K) andR^(13M) combine to form C═C; R^(13Y) is H or C₁₋₄ alkyl; R^(13Z) andR^(13Z) and R^(17Z′) are, independently, selected from H, halogen, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₇₋₁₄ alkaryl,C₃₋₁₀ alkcycloalkyl, and C₃₋₁₀ alkheterocyclyl; and X⁻ is anypharmaceutically acceptable anion. In some embodiments, the compound isselected from the group consisting of:

In another aspect, the invention features compounds according to thefollowing formula,

where n is an integer between 0-5; R^(14A) is heterocyclyl, each ofR^(14B), R^(14C), R^(14D), and R1^(4E) is, independently, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₇₋₁₄ alkaryl, C₃₋₁₀alkcycloalkyl, and C₃₋₁₀ alkheterocyclyl; and R^(14F) is selected fromH, halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl,C₇₋₁₄ alkaryl, C₃₋₁₀ alkcycloalkyl, and C₃₋₁₀ alkheterocyclyl, OR^(14G),NR^(14H)R^(14I), NR^(14J)C(O)R^(14K), S(O)R^(14L), SO₂R^(14M)R^(14N),SO₂NR^(14O)R^(14P), SO₃R^(14Q), CO₂R^(14R), C(O)R^(14S), andC(O)NR^(14T)R^(14V); and each of R^(14G)-R^(13AO) is independently,selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄heteroalkyl. In some embodiments, the compound is

where X is a pharmaceutically acceptable anion.

The invention also features pharmaceutical compositions that include acompound according to any of Formulas (XI)-(XIV), or any of compounds(1)-(563), and a pharmaceutically acceptable excipient. In someembodiments, the pharmaceutical composition is formulated for oral,nasal, or inhalation administration.

In certain embodiments, the compounds, compositions, methods, and kitsof the invention may be used to treat any disorder that is caused,wholly or in part, by neurogenic inflammation. Non-limiting examples ofsuch disorders include asthma, rhinitis, conjunctivitis, arthritis,colitis, contact dermatitis, pancreatitis, chronic cough, sinusisitis(e.g., chronic rhinosinusistis), traumatic brain injury, sepsis (e.g.,polymicrobial sepsis), tendinopathies chronic urticaria, rheumaticdisease, acute lung injury, exposure to irritants, inhalation ofirritants, pollutants or chemical warfare agents, eczema, cystitis,gastritis, urethritis, migraine headache, psoriasis, rhinitis, rosacea,sunburn, chemical warfare agents, inhaled tear gases, or inhaledpollutants.

Some methods and kits of the invention also feature one or moreacetaminophens, NSAIDs, glucocorticoids, narcotics, tricyclicantidepressants, amine transporter inhibitors, anticonvulsants,antiproliferative agents, or immune modulators.

In another embodiment, the compositions are administered byintraarticular, surgical, intravenous, intramuscular, oral, rectal,cutaneous, subcutaneous, topical, transdermal, sublingual, nasal,vaginal, intraurethral, intravesicular, intrathecal, epidural, mucosal,aural, or ocular administration by injection, inhalation, or directcontact. In yet another embodiment, the composition is formulated forcontrolled or sustained release over time.

By “biologically active” is meant that a molecule, including biologicalmolecules, such as nucleic acids, peptides, polypeptides, and proteins,exerts a physical or chemical activity on itself or other molecule. Forexample, a “biologically active” molecule may possess, e.g., enzymaticactivity, protein binding activity (e.g., antibody interactions), orcytotoxic activities (e.g., anti-cancer properties). Biologically activeagents that can be used in the methods and kits described hereininclude, without limitation, an antibody or antibody fragment, anantibiotic, a polynucleotide, a polypeptide, a protein, an anti-canceragent, a growth factor, and a vaccine.

By “inflammation” is meant any types of inflammation, such those causedby the immune system (immune-mediated inflammation) and by the nervoussystem (neurogenic inflammation), and any symptom of inflammation,including redness, heat, swelling, pain, and/or loss of function.

By “neurogenic inflammation” is meant any type of inflammation mediatedby neurons (e.g. nociceptors) or any other component of the central orperipheral nervous system.

By “patient” is meant any animal. In one embodiment, the patient is ahuman. Other animals that can be treated using the methods and kits ofthe invention include, but are not limited to, non-human primates (e.g.,monkeys, gorillas, chimpanzees), domesticated animals (e.g., horses,pigs, goats, rabbits, sheep, cattle, llamas), and companion animals(e.g., guinea pigs, rats, mice, lizards, snakes, dogs, cats, fish,hamsters, and birds).

Compounds useful in the invention include, but are not limited to, thosedescribed herein in any of their pharmaceutically acceptable forms,including isomers such as diastereomers and enantiomers, salts, esters,amides, thioesters, solvates, and polymorphs thereof, as well as racemicmixtures and pure isomers of the compounds described herein.

By “low molecular weight” is meant less than about 650 Daltons.

The term “pharmaceutically acceptable salt” represents those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or separately by reacting the free base function with asuitable organic acid. Representative acid addition salts include, butare not limited to, acetate, adipate, alginate, ascorbate, aspartate,benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate,camphersulfonate, citrate, cyclopentanepropionate, digluconate,dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate,glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide,hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, isethionate,lactobionate, lactate, laurate, lauryl sulfate, malate, maleate,malonate, mesylate, methanesulfonate, 2-naphthalenesulfonate,nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,toluenesulfonate, undecanoate, valerate salts, and the like. These acidaddition salts may also be referred to as “pharmaceutically acceptableanions.” Representative alkali or alkaline earth metal salts include,but are not limited to, sodium, lithium, potassium, calcium, magnesium,and the like, as well as nontoxic ammonium, quaternary ammonium, andamine cations, including, but not limited to ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, ethylamine, and the like.

In the generic descriptions of compounds of this invention, the numberof atoms of a particular type in a substituent group is generally givenas a range, e.g., an alkyl group containing from 1 to 4 carbon atoms orC₁₋₄ alkyl. Reference to such a range is intended to include specificreferences to groups having each of the integer number of atoms withinthe specified range. For example, an alkyl group from 1 to 4 carbonatoms includes each of C₁, C₂, C₃, and C₄. A C₁₋₁₂ heteroalkyl, forexample, includes from 1 to 12 carbon atoms in addition to one or moreheteroatoms. Other numbers of atoms and other types of atoms may beindicated in a similar manner.

As used herein, the terms “alkyl” and the prefix “alk-” are inclusive ofboth straight chain and branched chain groups and of cyclic groups,i.e., cycloalkyl. Cyclic groups can be monocyclic or polycyclic andpreferably have from 3 to 6 ring carbon atoms, inclusive. Exemplarycyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl groups.

By “C₁₋₄ alkyl” is meant a branched or unbranched hydrocarbon grouphaving from 1 to 4 carbon atoms. A C₁₋₄ alkyl group may be substitutedor unsubstituted. Exemplary substituents include alkoxy, aryloxy,sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl,perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino,hydroxyalkyl, carboxyalkyl, and carboxyl groups. C₁₋₄ alkyls include,without limitation, methyl, ethyl, n-propyl, isopropyl, cyclopropyl,cyclopropylmethyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, andcyclobutyl.

By “C₂₋₄ alkenyl” is meant a branched or unbranched hydrocarbon groupcontaining one or more double bonds and having from 2 to 4 carbon atoms.A C₂₋₄ alkenyl may optionally include monocyclic or polycyclic rings, inwhich each ring desirably has from three to six members. The C₂₋₄alkenyl group may be substituted or unsubstituted. Exemplarysubstituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio,halide, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl,disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, andcarboxyl groups. C₂₋₄ alkenyls include, without limitation, vinyl,allyl, 2-cyclopropyl-1-ethenyl, 1-propenyl, 1-butenyl, 2-butenyl,3-butenyl, 2-methyl-1-propenyl, and 2-methyl-2-propenyl.

By “C₂₋₄ alkynyl” is meant a branched or unbranched hydrocarbon groupcontaining one or more triple bonds and having from 2 to 4 carbon atoms.A C₂₋₄ alkynyl may optionally include monocyclic, bicyclic, or tricyclicrings, in which each ring desirably has five or six members. The C₂₋₄alkynyl group may be substituted or unsubstituted. Exemplarysubstituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio,halide, hydroxy, fluoroalkyl, perfluoralkyl, amino, aminoalkyl,disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, andcarboxyl groups. C₂₋₄ alkynyls include, without limitation, ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl.

By “C₂₋₆ heterocyclyl” is meant a stable 5- to 7-membered monocyclic or7- to 14-membered bicyclic heterocyclic ring which is saturatedpartially unsaturated or unsaturated (aromatic), and which consists of 2to 6 carbon atoms and 1, 2, 3 or 4 heteroatoms independently selectedfrom N, O, and S and including any bicyclic group in which any of theabove-defined heterocyclic rings is fused to a benzene ring. Theheterocyclyl group may be substituted or unsubstituted. Exemplarysubstituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio,halide, hydroxy, fluoroalkyl, perfluoralkyl, amino, aminoalkyl,disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, andcarboxyl groups. The nitrogen and sulfur heteroatoms may optionally beoxidized. The heterocyclic ring may be covalently attached via anyheteroatom or carbon atom which results in a stable structure, e.g., animidazolinyl ring may be linked at either of the ring-carbon atompositions or at the nitrogen atom. A nitrogen atom in the heterocyclemay optionally be quaternized. Preferably when the total number of S andO atoms in the heterocycle exceeds 1, then these heteroatoms are notadjacent to one another. Heterocycles include, without limitation,1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl,3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl,6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl,b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl,furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl,phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl,4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl,pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole,pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl,xanthenyl. Preferred 5 to 10 membered heterocycles include, but are notlimited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl,thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl,1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl,benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, andisoquinolinyl. Preferred 5 to 6 membered heterocycles include, withoutlimitation, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl,thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl,oxazolyl, isoxazolyl, and tetrazolyl.

By “C₆₋₁₂ aryl” is meant an aromatic group having a ring systemcomprised of carbon atoms with conjugated π electrons (e.g., phenyl).The aryl group has from 6 to 12 carbon atoms. Aryl groups may optionallyinclude monocyclic, bicyclic, or tricyclic rings, in which each ringdesirably has five or six members. The aryl group may be substituted orunsubstituted. Exemplary substituents include alkyl, hydroxy, alkoxy,aryloxy, sulfhydryl, alkylthio, arylthio, halide, fluoroalkyl, carboxyl,hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, monosubstituted amino,disubstituted amino, and quaternary amino groups.

By “C₇₋₁₄ alkaryl” is meant an alkyl substituted by an aryl group (e.g.,benzyl, phenethyl, or 3,4-dichlorophenethyl) having from 7 to 14 carbonatoms.

By “C₃₋₁₀ alkcycloalkyl” is meant an alkyl substituted by a cycloalkylgroup (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, or cyclooctyl) having from 3-10 carbon atoms.

By “C₃₋₁₀ alkheterocyclyl” is meant an alkyl substituted heterocyclicgroup having from 3 to 10 carbon atoms in addition to one or moreheteroatoms (e.g., 3-furanylmethyl, 2-furanylmethyl,3-tetrahydrofuranylmethyl, or 2-tetrahydrofuranylmethyl).

By “C₁₋₇ heteroalkyl” is meant a branched or unbranched alkyl, alkenyl,or alkynyl group having from 1 to 7 carbon atoms in addition to 1, 2, 3or 4 heteroatoms independently selected from the group consisting of N,O, S, and P. Heteroalkyls include, without limitation, tertiary amines,secondary amines, ethers, thioethers, amides, thioamides, carbamates,thiocarbamates, hydrazones, imines, phosphodiesters, phosphoramidates,sulfonamides, and disulfides. A heteroalkyl may optionally includemonocyclic, bicyclic, or tricyclic rings, in which each ring desirablyhas three to six members. The heteroalkyl group may be substituted orunsubstituted. Exemplary substituents include alkoxy, aryloxy,sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl,perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino,hydroxyalkyl, hydroxyalkyl, carboxyalkyl, and carboxyl groups. Examplesof C₁₋₇ heteroalkyls include, without limitation, methoxymethyl andethoxyethyl.

By “halide” is meant bromine, chlorine, iodine, or fluorine.

By “fluoroalkyl” is meant an alkyl group that is substituted with afluorine atom.

By “perfluoroalkyl” is meant an alkyl group consisting of only carbonand fluorine atoms.

By “carboxyalkyl” is meant a chemical moiety with the formula —(R)—COOH,wherein R is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₂₋₆heterocyclyl, C₆₋₁₂ aryl, C₇₋₁₄ alkaryl, C₃₋₁₀ alkheterocyclyl, or C₁₋₇heteroalkyl.

By “hydroxyalkyl” is meant a chemical moiety with the formula —(R)—OH,wherein R is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₂₋₆heterocyclyl, C₆₋₁₂ aryl, C₇₋₁₄ alkaryl, C₃₋₁₀ alkheterocyclyl, or C₁₋₇heteroalkyl.

By “alkoxy” is meant a chemical substituent of the formula —OR, whereinR is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₂₋₆heterocyclyl, C₆₋₁₂ aryl, C₇₋₁₄ alkaryl, C₃₋₁₀ alkheterocyclyl, or C₁₋₇heteroalkyl.

By “aryloxy” is meant a chemical substituent of the formula —OR, whereinR is a C₆₋₁₂ aryl group.

By “alkylthio” is meant a chemical substituent of the formula —SR,wherein R is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₂₋₆heterocyclyl, C₆₋₁₂ aryl, C₇₋₁₄ alkaryl, C₃₋₁₀ alkheterocyclyl, or C₁₋₇heteroalkyl.

By “arylthio” is meant a chemical substituent of the formula —SR,wherein R is a C₆₋₁₂ aryl group.

By “quaternary amino” is meant a chemical substituent of the formula—(R)—N(R′)(R″)(R′″)⁺, wherein R, R′, R″, and R′″ are each independentlyan optionally substituted alkyl, heteroalkyl, alkaryl, alkcycloalkyl,alkheterocyclyl, alkenyl, alkynyl, heteroaryl, or aryl group asdescribed herein. R may be an alkyl group linking the quaternary aminonitrogen atom, as a substituent, to another moiety. The nitrogen atom,N, is covalently attached to four carbon atoms of the alkyl,heteroalkyl, alkaryl, alkcycloalkyl, alkheterocyclyl, alkenyl, alkynyl,heteroaryl, and/or aryl groups, resulting in a positive charge at thenitrogen atom.

By “charged moiety” is meant a moiety which gains a proton atphysiological pH thereby becoming positively charged (e.g., ammonium,guanidinium, or amidinium) or a moiety that includes a net formalpositive charge without protonation (e.g., quaternary ammonium). Thecharged moiety may be either permanently charged or transiently charged.

As used herein, the term “parent” refers to a channel blocking compoundwhich can be modified by quaternization or guanylation of an aminenitrogen atom present in the parent compound. The quaternized andguanylated compounds are derivatives of the parent compound. Theguanidyl derivatives described herein are presented in their unchargedbase form. These compounds can be administered either as a salt (i.e.,an acid addition salt) or in their uncharged base form, which undergoesprotonation in situ to form a charged moiety.

By “therapeutically effective amount” means an amount sufficient toproduce a desired result, for example, the reduction or elimination ofneurogenic inflammation in a patient (e.g., a human) suffering from acondition, disease, or illness that is caused wholly or in part byneurogenic inflammation (e.g. asthma, arthritis, colitis, contactdermatitis, diabetes, eczema, cystitis, gastritis, migraine headache,psoriasis, rhinitis, rosacea, or sunburn).

Other features and advantages of the invention will be apparent from thefollowing detailed description, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the effect of intravenous QX-314 (0.4 mg/kg)on the edema elicited by injection of complete Freund's adjuvant (CFA)in the rat hindpaw determined by measuring the total volume of thehindpaw by plethysmography. The degree of swelling produced by injectionof CFA is reduced by administration of QX-314 reflecting reduction inneurogenic edema resulting from the blockade of nociceptors by QX314.QX-314 by itself has no effect different from administration of saline.

FIG. 2 shows the inhibition of voltage-dependent calcium channel currentin a dorsal root ganglion (DRG) neuron by N-methyl-verapamil applied inthe presence of capsaicin to open TRPV1 channels. Entry of the drug intothe cell, and its blocking action, depends on applying the drug in thepresence of capsaicin to activate the TRPV1 channels present in theneuronal membrane.

DETAILED DESCRIPTION OF THE INVENTION

The present invention features methods and kits for the treatment ofneurogenic inflammation by administering a positively-charged,voltage-gated ion channel inhibitor. In embodiments of the invention,the positively-charged, voltage-gated ion channel inhibitor isadministered alone or in combination with a TRP channel agonist such ascapsaicinoid (e.g. capsaicin), mustard oil, or a “caine” drug (e.g.,amylocaine, articaine, benzocaine, bupivacaine, carbocaine, carticaine,chloroprocaine, cyclomethycaine, dibucaine (cinchocaine), dimethocaine(larocaine), etidocaine, hexylcaine, levobupivacaine, lidocaine,mepivacaine, meprylcaine (oracaine), metabutoxycaine, piperocaine,prilocaine, procaine (novacaine), proparacaine, propoxycaine, risocaine,ropivacaine, tetracaine (amethocaine), or trimecaine).

Voltage-gated ion channels in pain-sensing neurons are currently ofgreat interest in developing strategies to treat neurogenicinflammation. Blocking voltage-dependent sodium channels in nociceptorscan reduce or eliminate neurogenic inflammation by preventing activationof nociceptor peripheral terminals and the release of pro-inflammatorychemicals. A limitation in designing small organic molecules thatinhibit sodium channels or calcium channels is that they must be activewhen applied externally to the target cell. The vast majority of suchexternally-applied molecules are hydrophobic and can pass through cellmembranes. Accordingly, such molecules will enter all cells and thusexhibit no selectivity for affecting only nociceptors.

Some inhibitors, such as the quarternary ammonium derivative QX-314, aremembrane-impermeant and are only effective when present inside thenociceptor cell, and thus must pass through the cell membrane via achannel or receptor, such as a transient receptor potential ion channel(TRP channels, e.g., TRPAV1, TRPA1, TRPM8, and P2X(2/3)), in order toproduce an effect. Under normal circumstances, most TRP channels innociceptors are not active but require a noxious thermal, mechanical, orchemical stimulus to activate them. For example, TRP channels innociceptors can be activated by an exogenous TRP ligand (i.e. TRPagonist) such as capsaicin, which opens the TRPV1 channel. Thus, oneapproach to selectively targeting nociceptors is to co-administer themembrane-impermeant ion channel inhibitor with an exogenous TRP ligandthat permits passage of the inhibitor through the TRP channel into thecell. In addition to capsaicin, the exogenous TRP ligand can also beanother capsaicinoid, mustard oil, or lidocaine. In another example, TRPchannels may be active in response to exogenous irritant activators suchas inhaled acrolein from smoke or chemical warfare agents such as teargas.

Under certain circumstances, TRP channels can be activated in theabsence of exogenous TRP activators/ligands by endogenous inflammatoryactivators that are generated by tissue damage, infection, autoimmunity,atopy, ischemia, hypoxia, cellular stress, immune cell activation,immune mediator production, and oxidative stress. Under such conditions,endogenous molecules (e.g., protons, lipids, and reactive oxygenspecies) can activate TRP channels expressed on nociceptors, allowingmembrane-impermeant, voltage-gated ion channel blockers to gain accessto the inside of the nociceptor through the endogenously-activated TRPchannels. Endogenous inflammatory activators of TRP channels include,for example, prostaglandins, nitric oxide (NO), peroxide (H₂O₂),cysteine-reactive inflammatory mediators like 4-hydroxynonenal,endogenous alkenyl aldehydes, endocannabinoids, and immune mediators(e.g., interleukin 1 (IL-1), nerve growth factor (NGF), and bradykinin).

Thus, the inventors have discovered that membrane-impermeant,positively-charged inhibitors of voltage-gated ion channels (e.g.,quarternary ammonium derivatives, such as QX-314), alone or incombination with an exogenous TRP ligand, can be used to selectivelytarget nociceptors in order to effectively treat (e.g., eliminate oralleviate) neurogenic inflammation in a patient (e.g., a human).

The invention is described in more detail below.

Neurogenic Inflammation

Inflammation is a complex set of responses to harmful stimuli thatresults in localized redness, swelling, and pain. Inflammation has twocomponents, one driven by antigens and mediated by immune cells(immune-mediated inflammation) and one mediated by the nervous system(neurogenic inflammation). Neurogenic inflammation results from theefferent functions of pain-sensing neurons (nociceptors), whereinneuropeptides and other chemicals that are pro-inflammatory mediatorsare released from the peripheral terminals of the nociceptors when theyare activated. This release process is mediated by calcium influx andexocytosis of vesicles, and the pro-inflammatory mediators includesubstance P, neurokinin A and B (collectively known as tachykinins), andcalcitonin gene-related peptide (CGRP).

The release of peripheral terminal chemicals stimulate a variety ofinflammatory responses. First, the release of substance P can result inan increase in capillary permeability such that plasma proteins leakfrom the intravascular compartment into the extracellular space (plasmaextravasation), causing edema. This can be detected as a wheal (a firm,elevated swelling of the skin) which is one component of a triad ofinflammatory responses—wheal, red spot, and flare—known as the Lewistriple response. Second, the release of CGRP causes vasodilation,leading to increased blood flow. This can be detected as a flare, whichis another component of the Lewis triple response.

Substance P also has a pro-inflammatory action on immune cells (e.g.macrophages, T-cells, mast cells, and dendritic cells) via theirneurokinin-1 (NK1) receptor. This effect has been documented in allergicrhinitis, gastitis, and colitis, and represents an interface between theneurogenic and immune-mediated components of inflammation. Substance Preleased from one nociceptor may also act on NK1 receptors onneighboring nociceptors to sensitize or activate them, causing a spreadof activation and afferent/efferent function.

These efferent functions of nociceptors can be triggered by: 1) Directactivation of a nociceptor terminal by a peripheral adequate stimulusapplied to the terminal (e.g. a pinch); 2) Indirect antidromicactivation of a non-stimulated nociceptor terminal by the axon reflex,wherein action potential input from one terminal of a nociceptor, uponreaching a converging axonal branch point in the periphery, results inan action potential traveling from the branch point down to theperipheral terminal of a non-stimulated terminal; and 3) Activation as aresult of activity in nociceptor central terminals in the CNS travelingto the periphery (e.g., primary afferent depolarization of centralterminals produced by GABA can be sufficient to initiate actionpotentials traveling the “wrong way”).

Neurogenic Inflammatory Disorders

In certain disorders, neurogenic inflammation contributes to theperipheral inflammation elicited by tissue injury, autoimmune disease,infection, and exposure to irritants in soft tissue, skin, therespiratory system, joints, the urogenital and GI tract, the liver, andthe brain. Neurogenic inflammatory disorders include asthma, rhinitis,conjunctivitis, arthritis, colitis, contact dermatitis, diabetes,eczema, cystitis, gastritis, migraine headache, psoriasis, rhinitis,rosacea, and sunburn, pancreatitis, chronic cough, chronicrhinosinusistis, traumatic brain injury, polymicrobial sepsis,tendinopathies chronic urticaria, rheumatic disease, acute lung injury,exposure to irritants, inhalation of irritants, pollutants, or chemicalwarfare agents, as described herein.

Asthma

Asthma is a chronic respiratory disorder that is characterized by airwayobstruction, bronchial hyperresponsiveness, and bronchial inflammation.Asthma can be induced by a variety of stimuli, including natural inhaledallergens (e.g. dust mites, pollen, and mold), household organiccompounds (e.g. soap, perfume, shampoo, creams, and lotions),medications, industrial chemicals, food allergies, exercise, hormonalchanges, and psychological stress. Patients who chronically suffer fromasthma experience episodes of hypersensitivity to such stimuli where thebronchi contract in spasms. During an asthma episode, inflammation ofthe airways causes bronchoconstriction and excess mucus production,making it difficult for the patient to breathe.

Cells responsible for airway hyperresponsiveness and obstruction includesensory and motor neurons as well as epithelial and smooth muscle cells.Asthma is the result of a complex set of interactions between thesecells and the immune system, particularly the T-helper-2 cells whichcontrol the inflammatory process. There is growing evidence thatcommunication between immune cells and neurons can be mediated byneurophilins, which are produced in increased concentrations by immunecells that enter the airways in an asthmatic episode. Neurophilinsmodify the functional activity of neuronal function, leading to alteredneuropeptide and tachykinin production that results in neurogenicinflammation. (Renz et al. Prog. Brain Res. 146:325, 2004.) TRPV1 andTRPA1 channels also contribute to the neurogenic component of allergicasthma as well as cough and rhinitis.

Arthritis

Arthritis is a group of conditions involving inflammation and damage tothe joints of the body. Arthritis can have many causes, includingphysical trauma and aging (osteoarthritis), autoimmune disease(rheumatoid arthritis and psoriatic arthritis), infection (septicarthritis), and gout (gouty arthritis).

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorderthat principally affects the joints (synovitis), characterized bydestruction of articular cartilage and bending/stiffness of the joints(ankylosis), and which leads to pain and substantial loss of mobility.RA can also cause inflammation in the skin, lungs, and kidneys. About 1%of the world population develops rheumatoid arthritis, with women havinga three-fold higher risk than men.

The causes of autoimmunity in RA are not fully understood, but evidencesuggests the involvement of abnormal B- and T-cell activation and therelease of TNF and other cytokines. There has also been a causal linkbetween cigarette smoke and RA. Studies have suggested that neurogenicinflammation makes an important contribution to the pathogenesis ofjoint pain in RA. See, for example, Levine et al. (J. Immunol. 135:843s,1985), which showed that the severity of joint injury in RA iscorrelated with a greater local concentration of substance P.

Colitis

Colitis is a group of chronic autoimmune disorders characterized byinflammation of the colon. Symptoms of colitis include pain, tendernessof the abdomen, fatigue, rapid weight loss, ulcers (ulcerative colitis),and gastrointestinal bleeding. Colitis can also be triggered by manyfoods, including alcohol, caffeine, dairy products, spicy foods, nuts,seeds, meats, refined sugar, and raw vegetables. It is known thatneurogenic mechanisms are important to the inflammatory processes incolitis. For example, studies have shown that induced colitisinflammation in mice can be mitigated using NK-1 and CGRP receptorantagonists. (Nguyen et al. Canadian J. Phys. Pharm. 81:920, 2003.)

Contact Dermatitis

Contact dermatitis is the local irritation of superficial regions of theskin caused by contact with irritants or allergens. In North America,the most common causes of allergic contact dermatitis are plants such aspoison ivy and poison oak. Common causes of irritant contact dermatitisare chemicals such as harsh soaps, detergents, and cleaning products.Symptoms of contact dermatitis include rash, blisters, wheals, hives,and burning itch. The role of neurogenic inflammation in contactdermatitis has been discussed, for example, in Guy, AMA Arch. Derm.Syphilol. 66:1, 1952.

Gastritis

Gastritis refers to a collection of disorders which induce inflammationof the stomach lining. Gastritis can be caused by excessive alcoholconsumption, prolonged use of NSAIDs such as aspirin or ibuprofen, andchronic infection by bacteria (primarily Helicobacter pylori). Certainautoimmune disorders can also cause gastritis. Symptoms include internalbleeding, pain (especially in the upper abdomen), vomiting, andbloating. Gastritis can also lead to increased risk of stomach cancer.

Migraine

Migraine is a neurological disorder, more common in women than in men,that is characterized by headache, nausea, and altered perception.Migraine proceeds in several phases: 1) a prodrome phase that includesfatigue, food craving, neck stiffness, altered mood, and constipation ordiarrhea; 2) an aura phase that includes disturbances of visionconsisting of white/multicolored flashes of lights or dazzling lines,feelings of “pins-and-needles” in the hand and arm, auditory/olfactoryhallucinations, vertigo, tingling/numbness of the face, andhypersensitivity to touch; 3) a pain phase that includes a throbbingheadache accompanied by nausea, vomiting, blurred vision, nasalstuffiness, diarrhea, and local edema; and 4) a postdrome phaseincluding fatigue and feelings of “hangover.”

There are many theories about the cause of migraine. Among these is thetheory that certain nerves, when irritated, release the pro-inflammatorymediators such as substance P that lead to neurogenic inflammation andassociated pain.

Rhinitis

Rhinitis, known commonly as the running nose, is a disorder involvingirritation and inflammation of internal nasal mucous membranes. Rhinitisis characterized by the generation of large amounts of mucus, producingrunning nose, nasal congestion, and post-nasal drip. According to recentestimates, more than 50 million people in the U.S. alone suffer fromrhinitis yearly. Rhinitis is categoried into infective rhinitis (causedby bacterial infection), nonallergic rhinitis (caused by hormones,drugs, and foods), and allergic rhinitis (caused by immune reactions toallergens, e.g. hayfever). The role of neurogenic inflammation in thepathogenesis of rhinitis is similar to that of asthma, whereenvironmental substances enhance the immune response, leading todownstream release of substance P from neurons.

Cystitis

Cystitis is inflammation of the urinary bladder. There are several typesof cystitis, including traumatic cystitis, interstitial cystitis,eosinophilic cystitis, radiation cystitis, and hemorrhagic cystitis.Interstitial cystitis, also known as painful bladder syndrome, is adisorder characterized by urination pain, urinary frequency, urgency,and pressure in the bladder. Unlike traumatic cystitis, interstitialcystitis has not been shown to be caused by bacterial infection. Thecause of interstitial cystitis is unknown but has been proposed toinvolve neurogenic inflammation. For example, animal studies have shownthat interstitial cystitis is correlated with both central andperipheral neural upregulation (Nazif et al., Urology 69:24-33 (2007)),and that acute bladder injury resulted in a significant increase in therelease of substance P and CGRP (Lucioni et al., BJU Int. 101:366-370,2008).

Additional Neurogenic Inflammatory Disorders

Additional neurogenic inflammatory disorders will be known to thoseskilled in the art, and include, but are not limited to sunburn,inflammatory conditions with a neurogenic component such as inflammationof blood vessels, eczema, rosacea, psoriasis, gingivitis, pancreatitis,chronic cough, chronic rhinosinusistis, traumatic brain injury,polymicrobial sepsis, tendinopathies chronic urticaria, acute lunginjury, exposure to irritants, inhalation of irritants, pollutants, orchemical warfare agents.

Inhibitors of Voltage-Gated Ion Channels

Inhibitors of voltage-gated ion channels that are suitable for use inthe methods and kits of the invention for the treatment of neurogenicinflammation are desirably positively-charged, hydrophilic compounds. Inone embodiment, the compounds are permanently charged (i.e., have acharge that is not transient). In another embodiment, the compounds aretransiently charged. Suitable inhibitors of voltage-gated sodiumchannels include, but are not limited to, QX-314, N-methyl-procaine(QX-222), N-octyl-guanidine, 9-aminoacridine, and pancuronium. Suitableinhibitors of voltage-gated calcium channels include, but are notlimited to, D-890 (quaternary methoxyverapamil), CERM 11888 (quaternarybepridil), N-methyl-verapamil, N-methylgallopamil, N-methyl-devapamil,dodecyltrimethylammonium, and other compounds as described herein (see,e.g., charged derivatives of the compounds described in Tables 1 and 2).

Additionally, there are many known inhibitors of voltage-gated ionchannels that would be of a suitable size to be useful in the methods ofthe invention (e.g., from about 100 to 4,000 Da, 100 to 3,000 Da, 100 to2,000 Da, 150 to 1,500 Da, or even 200 to 1,200 Da) and that have aminegroups, or can be modified to contain amine groups, that can be readilymodified to be charged (e.g., as positively-charged quarternary amines,or as transiently charged, e.g., guanylated, compounds). Such inhibitorsinclude, but are not limited to, riluzole, mexilitine, phenyloin,carbamazepine, procaine, tocainide, prilocaine, diisopyramide,bencyclane, quinidine, bretylium, lifarizine, lamotrigine, flunarizine,articaine, bupivicaine, mepivicaine, and fluspirilene.

Compounds that can be used in the methods and kits of the invention forthe treatment of inflammation include compounds of formulas I-X, below.

In formula I, each of R^(1A), R^(1B), and R^(1C) is, independently,selected from H, halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,OR^(1H), NR^(1I)R^(1J), NR^(1K)C(O)R^(1L), S(O)R^(1M), SO₂R^(1N)R^(1O),SO₂NR^(1P)R^(1Q), SO₃R^(1R), CO₂R^(1S), C(O)R^(1T), andC(O)NR^(1U)R^(1V); and each of R^(1H), R^(1I), R^(1K), R^(1L), R^(1M),R^(1N), R^(1O), R^(1P), R^(1Q), R^(1R), R^(1S), R^(1T), R^(1U), andR^(1V) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl X¹ is selected from —CR^(1W)R^(1X)—,—NR^(1Y)C(O)—, —OC(O)—, —SC(O)—, —C(O)NR^(1Z)—, —CO₂—, and —OC(S)—; andeach of R^(1W), R^(1Y), and R^(1Z) is, independently, selected from H,C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; R^(1D) isselected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄heteroalkyl; and each of R^(1E), R^(1F), and R^(1G) is, independently,selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄heteroalkyl; or R^(1D) and R^(1G) together complete a heterocyclic ringhaving at least one nitrogen atom. In a preferred embodiment, X¹ is—NHC(O)—. Exemplary compounds of formula I include methylated quaternaryammonium derivatives of anesthetic drugs, such as N-methyl lidocaine,N,N-dimethyl prilocaine, N,N,N-trimethyl tocainide, N-methyl etidocaine,N-methyl ropivacaine, N-methyl bupivacaine, N-methyl levobupivacaine,N-methyl mepivacaine. These derivatives can be prepared using methodsanalogous to those described in Scheme 1. Compounds of formula I includeQX-314 (CAS 21306-56-9) and QX-222 (CAS 21236-55-5) (below).

In formula II, each of R^(2A), R^(2B), and R^(2C) is, independently,selected from H, halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,OR^(2I), NR^(2J)R^(2K), NR^(2L)C(O)R^(2M), S(O)R^(2N), SO₂R^(2O)R^(2P),SO₂NR^(2Q)R^(2R), SO₃R^(2S), CO₂R^(2T), C(O)R^(2U), andC(O)NR^(2V)R^(2W); and each of R^(2I), R^(2J), R^(2K), R^(2L), R^(2M),R^(2N), R^(2O), R^(2P), R^(2Q), R^(2R), R^(2S), R^(2T), R^(2U), R^(2V),R^(2W) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; X² is selected from —CR^(2X)R^(2Y)—,—NR^(2Z)C(O)—, —OC(O)—, —SC(O)—, —C(O)NR^(2AA)—, —CO₂—, and —OC(S)—; andeach of R^(2X), R^(2Y), R^(2Z), and R^(2AA) is, independently, selectedfrom H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl;R^(2D) is selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, andC₂₋₄ heteroalkyl; R^(2E) is H or C₁₋₄ alkyl; and each of R^(2F), R^(2G),and R^(2H) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; or R^(2F) and R^(2G) togethercomplete a heterocyclic ring having two nitrogen atoms. Where R^(2F) andR^(2G) form a heterocyclic ring having two nitrogen atoms, the resultingguanidine group is, desirably, selected from

where R^(2H) is H or CH₃. Desirably, R^(2F) and R^(2G) combine to forman alkylene or alkenylene of from 2 to 4 carbon atoms, e.g., ringsystems of 5, 6, and 7-membered rings. In a preferred embodiment, X² is—NHC(O)—. Exemplary compounds of formula II include N-guanidylderivatives (e.g., —C(NH)NH₂ derivatives) of anesthetic drugs, such asdesethyl-N-guanidyl lidocaine, N-guanidyl prilocaine, N-guanidyltocainide, desethyl-N-guanidyl etidocaine, desbutyl-N-guanidylropivacaine, desbutyl-N-guanidyl bupivacaine, desbutyl-N-guanidyllevobupivacaine, desmethyl-N-guanidyl mepivacaine. These derivatives canbe prepared using methods analogous to those described in Schemes 2-5.

The guanidyl derivatives described herein (e.g., the compounds offormula II) are presented in their uncharged base form. These compoundscan be administered either as a salt (i.e., an acid addition salt) or intheir uncharged base form, which undergoes protonation in situ to form acharged moiety.

The synthesis of parent drugs of formulas I and II are described in theliterature. See, for example, U.S. Pat. No. 2,441,498 (synthesis oflidocaine), U.S. Pat. No. 3,160,662 (synthesis of prilocaine), DE PatentNo. 2235745 (synthesis of tocainide), DE Patent No. 2162744 (synthesisof etidocaine), PCT Publication No. WO85/00599 (synthesis ofropivacaine), U.S. Pat. No. 2,955,111 (synthesis of bupivacaine andlevobupivacaine), and U.S. Pat. No. 2,799,679 (synthesis ofmepivacaine).

In formula III, n=0-3 and m=0-3, with (n+m)=0-6; each of R^(3A), R^(3B),and R^(3C) is, independently, selected from H, halogen, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, OR^(3L), NR^(3M)R^(3N),NR^(3O)C(O)R^(3P), S(O)R^(3Q), SO₂R^(3R)R^(3S), SO₂NR^(3T)R^(3U),SO₃R^(3V), CO₂R^(3W), C(O)R^(3X), and C(O)NR^(3Y)R^(3Z); and each ofR^(3L), R^(3M), R^(3N), R^(3O), R^(3P), R^(3Q), R^(3R), R^(3S), R^(3T),R^(3U), R^(3V), R^(3W), R^(3X), R^(3Y), R^(3Z) is, independently,selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄heteroalkyl; Y³ is selected from —CR^(3AA)R^(3AB)—, —NR^(3AC)C(O)—,—OC(O)—, —SC(O)—, —C(O)NR^(3AD)—, —CO₂—, and —OC(S)—; and each ofR^(3AA), R^(3AB), R^(3AC), and R^(3AD) is, independently, selected fromH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; each ofR^(3D), R^(3E), R^(3F), and R^(3G) is, independently, selected from H,C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₂₋₆heterocyclyl, C₆₋₁₂ aryl, C₇₋₁₄ alkaryl, and C₃₋₁₀ alkheterocyclyl; eachof R^(3H), R^(3J), and R^(3K) is, independently, selected from C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl. The quaternarynitrogen in formula III is identified herein as N′. Exemplary compoundsof formula III include methylated quaternary ammonium derivatives ofanesthetic drugs, such as N′-methyl procaine, N′-methyl proparacaine,N′-methyl allocain, N′-methyl encainide, N′-methyl procainamide,N′-methyl metoclopramide, N′-methyl stovaine, N′-methyl propoxycaine,N′-methyl chloroprocaine, N′,N′-dimethyl flecainide, and N′-methyltetracaine. These derivatives can be prepared using methods analogous tothose described in Scheme 1.

In formula IV, n=0-3 and m=0-3, with (n+m)=0-6; each of R^(4A) andR^(4B) is, independently, selected from H, halogen, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, OR^(4L), NR^(4M)R^(4N),NR^(4O)C(O)R^(4P), S(O)R^(4Q), SO₂R^(4R)R^(4S)SO₂NR^(4T)R^(4U),SO₃R^(4V), CO₂R^(4W), C(O)R^(4X), and C(O)NR^(4Y)R^(4Z); and each ofR^(4L), R^(4M)R^(4N), R^(4O), R^(4P), R^(4Q), R^(4R), R^(4S), R^(4T),R^(4U), R^(4V), R^(4W), R^(4X), R^(4Y), and R^(4Z) is independently,selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄heteroalkyl; Y⁴ is selected from —CR^(4AA)R^(4AB)—, —NR^(4AC)C(O)—,—OC(O)—, —SC(O)—, —C(O)NR^(4AD)—, —CO₂—, and —OC(S)—; and each ofR^(4AA), R^(4AB), R^(4AC), and R^(4AD) is, independently, selected fromH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; each ofR^(4C), R^(4D), R^(4E), and R^(4F) is, independently, selected from H,C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₂₋₆heterocyclyl, C₆₋₁₂ aryl, C₇₋₁₄ alkaryl, and C₃₋₁₀ alkheterocyclyl; X⁴is selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, andNR^(4J)R^(4K); each of R^(4J) and R^(4K) (is, independently, selectedfrom H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl;and each of R^(4G), R^(4H), and R^(4I) is, independently, selected fromC₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl. Thequaternary nitrogen in formula IV is identified herein as N″. Exemplarycompounds of formula III include methylated quaternary ammoniumderivatives of anesthetic drugs, such as N″,N″,N″-trimethyl procaine,N″,N″,N″-trimethyl proparacaine, N″,N″,N″-trimethyl procainamide,N″,N″,N″-trimethyl metoclopramide, N″,N″,N″-trimethyl propoxycaine,N″,N″,N″-trimethyl chloroprocaine, N″,N″-dimethyl tetracaine,N″,N″,N″-trimethyl benzocaine, and N″,N″,N″-trimethyl butamben. Thesederivatives can be prepared using methods analogous to those describedin Scheme 1.

In formula V, n=0-3 and m=0-3, with (n+m)=0-6; each of R^(5A), R^(5B),and R^(5C) is, independently, selected from H, halogen, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, OR^(5M), NR^(5N)R^(5O),NR^(5P)C(O)R^(5Q), S(O)R^(5R), SO₂R^(5S)R^(5T), SO₂NR^(5U)R^(5V),SO₃R^(5W), CO₂R^(5X), C(O)R^(5Y), and C(O)NR^(5Z)R^(5AA); and each ofR^(5M), R^(5N), R^(5O), R^(5P), R^(5Q), R^(5R), R^(5S), R^(5T), R^(5U),R^(5V), R^(5W), R^(5X), R^(5Y), R^(5Z), and R^(5AA) is, independently,selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄heteroalkyl; Y⁵ is selected from —CR^(5AB)R^(5AC)—, —NR^(5AD)C(O)—,—OC(O)—, —SC(O)—, —C(O)NR^(5AE)—, —CO₂—, and —OC(S)—; and each ofR^(5AB), R^(5AC), R^(5AD), and R^(5AE) is, independently, selected fromH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; each ofR^(5D), R^(5E), R^(5F), and R^(5G) is, independently, selected from H,C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₂₋₆heterocyclyl, C₆₋₁₂ aryl, C₇₋₁₄ alkaryl, and C₃₋₁₀ alkheterocyclyl;R^(5H) is H or C₁₋₄ alkyl; and each of R^(5J), R^(5K), and R^(5L) is,independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,and C₂₋₄ heteroalkyl; or R^(5J) and R^(5K) together complete aheterocyclic ring having two nitrogen atoms. Where R^(5J) and R^(5K)form a heterocyclic ring having two nitrogen atoms, the resultingguanidine group is, desirably, selected from

where R^(5L) is H or CH₃. Desirably, R^(5J) and R^(5K) combine to forman alkylene or alkenylene of from 2 to 4 carbon atoms, e.g., ringsystems of 5, 6, and 7-membered rings. The guanylated nitrogen informula V is identified herein as N′. Exemplary compounds of formula Vinclude N-guanidyl derivatives (e.g., —C(NH)NH₂ derivatives) ofanesthetic drugs, such as such as desethyl-N′-guanidyl procaine,desethyl-N′-guanidyl proparacaine, desethyl-N′-guanidyl allocain,desmethyl-N′-guanidyl encainide, desethyl-N′-guanidyl procainamide,desethyl-N′-guanidyl metoclopramide, desmethyl-N′-guanidyl stovaine,desethyl-N′-guanidyl propoxycaine, desethyl-N′-guanidyl chloroprocaine,N′-guanidyl flecainide, and desethyl-N′-guanidyl tetracaine. Thesederivatives can be prepared using methods analogous to those describedin Schemes 2-5.

In formula VI, n=0-3 and m=0-3, with (n+m)=0-6; each of R^(6A) andR^(6B) is, independently, selected from H, halogen, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, OR^(6K), NR^(6L)R^(6M),NR^(6N)C(O)R^(6O), S(O)R^(6P), SO₂R^(6Q)R^(6R), SO₂NR^(6S)R^(6T),SO₃R^(6U), CO₂R^(6V), C(O)R^(6W), and C(O)NR^(6X)R^(6Y); and each ofR^(6K), R^(6L), R^(6M), R^(6N), R^(6O), R^(6P), R^(6Q), R^(6R), R^(6S),R^(6T), R^(6U), R^(6V), R^(6W), R^(6X), and R^(6Y) is, independently,selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄heteroalkyl; Y⁶ is selected from —CR^(6Z)R^(6AA)—, —NR^(6AB)C(O)—,—OC(O)—, —SC(O)—, —C(O)NR^(6AC), —CO₂—, and —OC(S)—; and each of R^(6Z),R^(6AA), R^(6AB), and R^(6AC) is, independently, selected from H, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; each of R^(6C),R^(6D), R^(6E), and R^(6F) is, independently, selected from H, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₂₋₆ heterocyclyl,C₆₋₁₂ aryl, C₇₋₁₄ alkaryl, and C₃₋₁₀ alkheterocyclyl; X⁶ is selectedfrom H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and NR^(6AD)R^(6AE);each of R^(6AD) and R^(6AE) is, independently, selected from H, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; R^(6G) is H orC₁₋₄ alkyl; and each of R^(6H), R^(6I), and R^(6J) is, independently,selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄heteroalkyl; or R^(6H) and R^(6I) together complete a heterocyclic ringhaving two nitrogen atoms. Where R^(6H) and R^(6I) form a heterocyclicring having two nitrogen atoms, the resulting guanidine group is,desirably, selected from

where R^(6J) is H or CH₃. Desirably, R^(6H) and R^(6I) combine to forman alkylene or alkenylene of from 2 to 4 carbon atoms, e.g., ringsystems of 5, 6, and 7-membered rings. The guanylated nitrogen informula V is identified herein as N″. Exemplary compounds of formula VIinclude N-guanidyl derivatives (e.g., —C(NH)NH₂ derivatives) ofanesthetic drugs, such as such as N″-guanidyl procaine, N″-guanidylproparacaine, N″-guanidyl procainamide, N″-guanidyl metoclopramide,N″-guanidyl propoxycaine, N″-guanidyl chloroprocaine, N″-guanidyltetracaine, N″-guanidyl benzocaine, and N″-guanidyl butamben. Thesederivatives can be prepared using methods analogous to those describedin Schemes 2-5.

The synthesis of parent drugs of formulas III-VI are described in theliterature. See, for example, U.S. Pat. No. 812,554 (synthesis ofprocaine), Clinton et al., J. Am. Chem. Soc. 74:592 (1952) (synthesis ofproparacaine), U.S. Pat. No. 2,689,248 (synthesis of propoxycaine),Hadicke et al., Pharm. Zentralh. 94:384 (1955) (synthesis ofchloroprocaine), U.S. Pat. No. 1,889,645 (synthesis of tetracaine),Salkowski et al., Ber. 28:1921 (1895) (synthesis of benzocaine), Brillet al., J. Am. Chem. Soc. 43:1322 (1921) (synthesis of butamben), U.S.Pat. No. 3,931,195 (synthesis of encainide), Yamazaki et al., J. Pharm.Soc. Japan 73:294 (1953) (synthesis of procainamide), U.S. Pat. No.3,177,252 (synthesis of metoclopramide), U.S. Pat. No. 3,900,481(synthesis of flecainide), and Fourneau et al., Bull. Sci. Pharmacol.35:273 (1928) (synthesis of stovaine), each of which is herebyincorporated by reference.

In formula VII, n=0-3 and m=0-3, with (n+m)=0-6; each of R^(7A), R^(7B),and R^(7C) is, independently, selected from H, halogen, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, OR^(7L), NR^(7M)R^(7N),NR^(7O)C(O)R^(7P), S(O)R^(7Q), SO₂R^(7R)R^(7S), SO₂NR^(7T)R^(7U),SO₃R^(7V), CO₂R^(7W), C(O)R^(7X), and C(O)NR^(7Y)R^(7Z); and each ofR^(7L), R^(7M), R^(7N), R^(7O), R^(7P), R^(7Q), R^(7R), R^(7S), R^(7T),R^(7U), R^(7V), R^(7W), R^(7X), R^(7Y), and R^(7Z) is, independently,selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄heteroalkyl; X⁷ is selected from —CR^(7AA)R^(7AB)—, NR^(7AC)(O)—,—OC(O)—, —SC(O)—, —C(O)NR^(7AD)—, —CO₂—, and —OC(S)—; and each ofR^(7AA), R^(7AB), R^(7AC), and R^(7AD) is, independently, selected fromH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; each ofR^(7D), R^(7E), R^(7F), and R^(7G) is, independently, selected from H,C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₂₋₆heterocyclyl, C₆₋₁₂ aryl, C₇₋₁₄ alkaryl, and C₃₋₁₀ alkheterocyclyl; andeach of R^(7H), R^(7I), and R^(7K) is, independently, selected from C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl. In a preferredembodiment, X⁷ is —C(O)NH—. Exemplary compounds of formula VII includemethylated quaternary ammonium derivatives of anesthetic drugs, such asN′-methyl dibucaine. These derivatives can be prepared using methodsanalogous to those described in Scheme 1.

In formula VIII, n=0-3 and m=0-3, with (n+m)=0-6; each of R^(8A),R^(8B), and R^(8C) is, independently, selected from H, halogen, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, OR^(8L),NR^(8M)R^(8N), NR^(8O)C(O)R^(8P), S(O)R^(8Q), SO₂R^(8R)R^(8S),SO₂NR^(8T)R^(8U), SO₃R^(8V), CO₂R^(8W), C(O)R^(8X), andC(O)NR^(8Y)R^(8Z); and each of R^(8L), R^(8M), R^(8N), R^(8O), R^(8P),R^(8Q), R^(8R), R^(8S), R^(8T), R^(8U), R^(8V), R^(8W), R^(8X), R^(8Y),and R^(8Z) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; X⁸ is selected

from —CR^(8AA)R^(8AB)—, —NR^(8AC)C(O)—, —OC(O)—, —SC(O)—, —C(O)NR^(8AD),—CO₂—, and —OC(S)—; and each of R^(8AA), R^(8AB), R^(8AC), and R^(8AD)is independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, and C₂₋₄ heteroalkyl; each of R^(8D), R^(8E), R^(8F), andR^(8G) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₂₋₆ heterocyclyl, C₆₋₁₂ aryl, C₇₋₁₄alkaryl, and C₃₋₁₀ alkheterocyclyl; R^(8H) is H or C₁₋₄ alkyl; and eachof R^(8I), R^(8J), and R^(8K) is, independently, selected from H, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; or R^(8I) andR^(8J) together complete a heterocyclic ring having two nitrogen atoms.Where R^(8I) and R^(8J) form a heterocyclic ring having two nitrogenatoms, the resulting guanidine group is, desirably, selected from

where R^(8K) is H or CH₃. Desirably, R^(8I) and R^(8J) combine to forman alkylene or alkenylene of from 2 to 4 carbon atoms, e.g., ringsystems of 5, 6, and 7-membered rings. The guanylated nitrogen informula V is identified herein as N′. In a preferred embodiment, X⁸ is—C(O)NH—. Exemplary compounds of formula VIII include N-guanidylderivatives (e.g., —C(NH)NH₂ derivatives) of anesthetic drugs, such assuch as desethyl-N-guanidyl dibucaine. These derivatives can be preparedusing methods analogous to those described in Schemes 2-5.

In formula IX, n=0-6; each of R^(9A), R^(9B), R^(9C), R^(9D), and R^(9E)is independently, selected from H, halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, OR^(9I), NR^(9J)R^(9K), NR^(9L)C(O)R^(9M), S(O)R^(9N),SO₂R^(9O)R^(9P), SO₂NR^(9Q)R^(9R), SO₃R^(9S), CO₂R^(9T), C(O)R^(9U), andC(O)NR^(9V)R^(9W); and each of R^(9I), R^(9J), R^(9K), R^(9L), R^(9M),R^(9N), R^(9O), R^(9P), R^(9Q), R^(9R), R^(9S), R^(9T), R^(9U), R^(9V),and R^(9W) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; X⁹ is selected from —CR^(9X)R^(9Y)—,—O—, —S—, and —NR^(9Z)—; and each of R^(9X), R^(9Y), and R^(9Z) is,independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,and C₂₋₄ heteroalkyl; Y⁹ is NR^(9AA)NR^(9AB)NR^(9AC) or NR^(9AD)Z⁹; eachof R^(9AA), R^(9AB), and R^(9AC) is, independently, selected from H,C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl; R^(9AD) is H or C₁₋₄ alkyl;Z⁹ is

andeach of R^(9F), R^(9G), and R^(9H) is, independently, selected from H,C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, or R^(9F) and R^(9G)together complete a heterocyclic ring having two nitrogen atoms. WhereR^(9F) and R^(9G) form a heterocyclic ring having two nitrogen atoms,the resulting guanidine group is, desirably, selected from

where R^(9H) is H or CH₃. Desirably, R^(9F) and R^(9G) combine to forman alkylene or alkenylene of from 2 to 4 carbon atoms, e.g., ringsystems of 5, 6, and 7-membered rings. In a preferred embodiment,X⁹═—O—. Exemplary compounds of formula IX include N-guanidyl derivatives(e.g., —C(NH)NH₂ derivatives), such as N-guanidyl fluoxetine, andmethylated quaternary ammonium derivatives, such as N,N-dimethylfluoxetine. These derivatives can be prepared using methods analogous tothose described in Schemes 1-5.

In formula X, W₃ is O, NH, NCH₂R^(10J), NC(O)CH₂R^(10J), CHCH₂R^(10J),C═CHR^(10J), or C═CHR^(10K); W₁-W₂ is S, O, OCHR^(10K), SCHR^(10K),N═CR^(10K), CHR^(10L)—CHR^(10K), or CR^(10L)═CR^(10K); each of R^(10A),R^(10B), R^(10C), R^(10D), R^(10E), R^(10F), R^(10G), and R^(10H) is,independently, selected from H, OH, halide, C₁₋₄ alkyl, and C₂₋₄heteroalkyl; R^(10J) is CH₂CH₂X^(10A) or CH(CH₃)CH₂X^(10A); R^(10L) is Hor OH; R^(10K) is H, OH, or the group:

X^(10A) is NR^(10M)R^(10N)R^(10P), or NR^(10Q)X^(10C); X^(10B) isNR^(10R)R^(10S), or NX^(10C); each of R^(10M), R^(10N), R^(10P),R^(10R), and R^(10S) is, independently, selected from C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl, or R^(10R), and R^(10S)together complete a heterocyclic ring having at least one nitrogen atom;R^(10Q) is H or C₁₋₄ alkyl; X^(10C) is

andeach of R^(10T), R^(10U), and R^(10V) is, independently, selected fromH, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, or R^(10T) and R^(10V)together complete a heterocyclic ring having two nitrogen atoms. WhereR^(10T) and R^(10V) form a heterocyclic ring having two nitrogen atoms,the resulting guanidine group is, desirably, selected from

where R^(10U) is H or CH₃. Desirably, R^(10T) and R^(10V) combine toform an alkylene or alkenylene of from 2 to 4 carbon atoms, e.g., ringsystems of 5, 6, and 7-membered rings. Exemplary compounds of formula Xinclude N-guanidyl derivatives (e.g., —C(NH)NH₂ derivatives) andmethylated quaternary ammonium derivatives. N-guanidyl derivatives offormula X include, without limitation, N-guanidyl amoxapine,desmethyl-N-guanidyl trimipramine, desmethyl-N-guanidyl dothiepin,desmethyl-N-guanidyl doxepin, desmethyl-N-guanidyl amitriptyline,N-guanidyl protriptyline, N-guanidyl desipramine, desmethyl-N-guanidylclomipramine, desmethyl-N-guanidyl clozapine, desmethyl-N-guanidylloxapine, N-guanidyl nortriptyline, desmethyl-N-guanidylcyclobenzaprine, desmethyl-N-guanidyl cyproheptadine,desmethyl-N-guanidyl olopatadine, desmethyl-N-guanidyl promethazine,desmethyl-N-guanidyl trimeprazine, desmethyl-N-guanidyl chlorprothixene,desmethyl-N-guanidyl chlorpromazine, desmethyl-N-guanidyl propiomazine,desmethyl-N-guanidyl prochlorperazine, desmethyl-N-guanidylthiethylperazine, desmethyl-N-guanidyl trifluoperazine,desethyl-N-guanidyl ethacizine, and desmethyl-N-guanidyl imipramine.Methylated quaternary ammonium derivatives of formula X include, withoutlimitation, N,N-dimethyl amoxapine, N-methyl trimipramine, N-methyldothiepin, N-methyl doxepin, N-methyl amitriptyline, N,N-dimethylprotriptyline, N,N-dimethyl desipramine, N-methyl clomipramine, N-methylclozapine, N-methyl loxapine, N,N-dimethyl nortriptyline, N-methylcyclobenzaprine, N-methyl cyproheptadine, N-methyl olopatadine, N-methylpromethazine, N-methyl trimeprazine, N-methyl chlorprothixene, N-methylchlorpromazine, N-methyl propiomazine, N-methyl moricizine, N-methylprochlorperazine, N-methyl thiethylperazine, N-methyl fluphenazine,N-methyl perphenazine, N-methyl flupenthixol, N-methyl acetophenazine,N-methyl trifluoperazine, N-methyl ethacizine, and N-methyl imipramine.These derivatives can be prepared using methods analogous to thosedescribed in Schemes 1-5.

Other ion channel blockers that can contain an amine nitrogen which canbe guanylated or quaternized as described herein include, withoutlimitation, orphenadrine, phenbenzamine, bepridil, pimozide,penfluridol, flunarizine, fluspirilene, propiverine, disopyramide,methadone, tolterodine, tridihexethyl salts, tripelennamine, mepyramine,brompheniramine, chlorpheniramine, dexchlorpheniramine, carbinoxamine,levomethadyl acetate, gallopamil, verapamil, devapamil, tiapamil,emopamil, dyclonine, pramoxine, lamotrigine, fendiline, mibefradil,gabapentin, amiloride, diltiazem, nifedipine, nimodipine, nitrendipine,cocaine, mexiletine, propafenone, quinidine, oxethazaine, articaine,riluzole, bencyclane, lifarizine, and strychnine. Still other ionchannel blockers can be modified to incorporate a nitrogen atom suitablefor quaternization or guanylation. These ion channel blockers include,without limitation, fosphenyloin, ethotoin, phenyloin, carbamazepine,oxcarbazepine, topiramate, zonisamide, and salts of valproic acid.

Examples of these channel blockers, including still other derivativesthat can be quaternized or guanylated according to the methods describedherein are provided in Table 1.

TABLE 1 No. Channel Blocker Exemplary References 1 orphenadrine U.S.Pat. No. 2,567,351 (see, e.g., the compounds of Examples 1-6 and theformula described at col.1, lines 10-24). U.S. Pat. No. 2,991,225 (see,e.g., the structure shown at col. 1, line 25). 2 phenbenzamine (RP-Passalacqua et al., “Structure and 2339; Antergan ®), Classification ofH₁-Antihistamines and Overview of Their Activities,” in Histamine andH1-antihistamines in Allergic Disease, F.E.R. Simons, Ed., InformaHealth Care (2002). 3 bepridil U.S. Pat. No. 3,962,238 (see, e.g.,Formulas I-V and compounds 1-6 of Table 1). US RE30577 4 pimozide See,e.g., Janssen et al., Arzneimittel- Forsch. 18: 261, 279, 282 (1968),and Journal of Neuroscience, 22(2): 396-403 (2002) 5 penfluridol U.S.Pat. No. 3,575,990 (see, e.g., the compounds of Formula (I), claims 1-7,and Examples I-XXXIII). 6 flunarizine U.S. Pat. No. 3,773,939 (see,e.g., Formula (I) and the compound described at col. 5, line 40). 7fluspirilene U.S. Pat. No. 3,238,216 (see, e.g., the compounds recitedin any of claims 1- 34). 8 propiverine DD 106643 9 disopyramide U.S.Pat. No. 3,225,054 (see, e.g., the compounds of Examples 1-15 and claims1-3) 10 methadone DE711069 U.S. Pat. No. 2,983,757 11 tolterodine U.S.Pat. No. 5,382,600 (see, e.g., Formula (I), the compounds described atcol.3, lines 20-39, in Table 1, and in claims 1-7) 12 tridihexethylsalts U.S. Pat. No. 2,913,494 (see, e.g., col. 1, lines 15-22) 13tripelennamine U.S. Pat. No. 2,502,151 (see, e.g., Formula (I) and thecompounds recited in claims 1-13) 14 mepyramine U.S. Pat. No. 2,502,151(pyrilamine) 15 brompheniramine U.S. Pat. No. 2,567,245 (see, e.g., theformula described at col. 1, lines 30-45, the compounds of ExamplesI-XXI, and the compounds recited in claims 1-15) U.S. Pat. No. 2,676,964(see, e.g., the formula described at col.1, lines 5-28, the compounds ofExamples I-XLIV, and the compounds recited in claims 1- 14) U.S. Pat.No. 3,061,517 (see, c.g., the formula at col.1, lines 49-67, and thecompounds described at col. 2, lines 17- 19, col. 2, lines 40-43, col.4, lines 2-7, and claims 1-6) 16 chlorpheniramine U.S. Pat. No.2,567,245 (see, e.g., the 17 dexchlorpheniramine formula described atcol. 1, lines 30-45, the compounds of Examples I-XXI, and the compoundsrecited in claims 1-15) U.S. Pat. No. 2,676,964 (see, e.g., the formuladescribed at col.1, lines 5-28, the compounds of Examples I-XLIV, andthe compounds recited in claims 1- 14) U.S. Pat. No. 3,061,517 (see,e.g., the formula at col.1, lines 49-67, and the compounds described atcol. 2, lines 17- 19, col. 2, lines 40-43, col. 4, lines 2-7, and claims1-6)U.S. Pat. No. 2,766,174 (see, e.g., the formula described at col. 1,lines 41-72) 18 carbinoxamine U.S. Pat. No. 2,606,195 (see, e.g., theformula described at col. 1, lines 7-24, Examples I-VIII, and in claims1-3) U.S. Pat. No. 2,800,485 GB 905993 19 levomethadyl acetate Pohlandet al., J. Am. Chem. Soc. 71: 460 (1949) 20 gallopamil U.S. Pat. No.3,261,859 (see, e.g., Formula (I), Examples 1-28, and claims 1-19)Theodore et al., J. Org. Chem. 52: 1309 (1987) 21 verapamil U.S. Pat.No. 3,261,859 (see, e.g., Formulas (I) and (IV), Examples 1-28, andclaims 1-19) 22 devapamil Godfraind, Calcium Channel Blockers, 23tiapamil Birkhauser Verlag (January 2004). 24 emopamil 25 dyclonincPofft, Chem. Tech. (Berlin) 4: 241 (1952) 26 pramoxine U.S. Pat. No.2,870,151 (see, e.g., the formula described at col.1, lines 18-25, andthe compounds of Examples I-XII and claims 1-13). 27 lamotrigine EP21121U.S. Pat. No. 4,602,017 (see, e.g., Formulas (I)-(III) and the compoundsdescribed at col. 2, line 63-col. 3, line 12, Examples 1-5, and claims1-2) 28 mibefradil U.S. Pat. No. 4,808,605 (see, e.g., Formula Idescribed at col.1, lines 10- 33 and the compounds described at col. 3,line 58-col. 7, line 6, Examples 1-41, and claims 1-15). 29 gabapentinU.S. Pat. No. 4,024,175 (see, e.g., Formula (I) described at col.1,lines 5- 17, Examples 1-12, and claims 1-11) 30 amiloride U.S. Pat. No.3,313,813 (see, e.g., the compounds described at col. 1, line 13- col.2,line 55, Examples 1-205, and claims 1-31) 31 diltiazem U.S. Pat. No.3,562,257 (see, e.g., Formula (I) described at col.1, lines 39- 64, andthe compounds described at col. 2, lines 15-30, Tables 1-3, and claims1- 43) U.S. Pat. No. 4,552,695 (see, e.g., the compound of Formula (I))32 nifedipine U.S. Pat. No. 3,485,847 (see, e.g., the Formula describedat col. 1, line 40-col. 2, line 6, the compounds of Examples 1-6, andclaims 1-27) 33 nimodipine U.S. Pat. No. 3,799,934 (see, e.g., theFormula described at col. 1, lines 39- 69, the compounds described atcol. 4, line 50-col. 5, line 16, Examples 1-53, and claims 1-13) 34nitrendipine 35 mexiletine U.S. Pat. No. 3,954,872 (see, e.g., Formula(I) described at col.1, lines 14- 35, and the compounds of Examples 1- 6and claims 1-4) 36 propafenone DE2001431 (see, e.g., claims 1-4) 37quinidine Turner et al., The Alkaloids, Vol. 3, 1- 63 (1953) Mason etal., Ann. N.Y. Acad. Sci. 432: 162-176 (1984) 38 oxethazaine U.S. Pat.No. 2,780,646 (see, e.g., the formula described at col. 1, lines 18-42,and the compounds of Examples 1-14 and claims 1-8) 39 articaine Beckeret al., Anesth Prog. 53(3): 98- 109 (Fall 2006) 40 riluzole U.S. Pat.No. 4,370,338 (see, e.g., the compound described at col. 1, line 15) 41bencyclane HU 151865 42 lifarizine Grauert et al., J. Med. Chem. 45(17):3755-3764 (2002) 43 strychnine Makarevich et al., “Quaternary salts ofalkaloids,”Vol. 42, pages 473-476, Chemistry of Natural Compounds,Springer New York: 2006. 44 fendiline U.S. Pat. No. 3,262,977 (see,e.g., Formula (I), Examples 1-9, and the compounds of claims 1-9)

Calcium-Channel Blockers

Exemplary cationic calcium channel blockers include D-890, CERM 11888,N-methyl-verapamil, N-methylgallopamil, N-methyl-devapamil, anddodecyltrimethylammonium. Other exemplary compounds include any chargedderivative, e.g., a quarternary amine derivative, of verapamil,gallopamil, devapamil, diltiazem, fendiline, mibefradil, terpenecompounds (e.g., sesquiterpenes) such as those described in Norman etal. Agricultural and Biological Chemistry 49(10):2893-8 (1985), andother inhibitors of calcium channels (see, for example, Triggle,European Journal of Pharmacology, 375:311-325 (1999), Eller et al.,British Journal of Pharmacology, 130:669-677 (2000), and Yamamoto etal., Current Topics in Medicinal Chemistry, 9:377-395 (2009), which canbe prepared according to the methods described herein.

For example, Yamamoto et al. provides the following N-type calciumchannel blockers (Table 2), which can be modified (e.g., quaternized orguanylated) according to the methods described herein.

TABLE 2 No. Channel Blocker Exemplary References 45

Yamamoto et al., Bioorg. Med. Chem.14:5333-5339 (2006). 46

Yamamoto et al., Bioorg. Med. Chem. Lett. 16:798-802 (2006). 47

Yamamoto et al., Bioorg. Med. Chem. Lett. 18:4813- 4815 (2008). 48

See, e.g., WO08143263 and EP2149560 (e.g., Formula (I), the compounds ofTables 6- 35, 43-110, 126-127, and the compounds of claims 1-6) 49

Miller et al., Soc. Neurosci. Abstr. 25(Part 2):896.3 (1999) 50

WO0236567 (see, e.g., formulas I-IV, the compounds of Table 2 (Examples1-111), and claims 1-5) 51

Zhang et al., Eur. J. Pharmacol. 587:24-47 (2008) 52

Baell et al., Bioorg. Med. Chem. 12:4025-4037 (2004) 53

Yamamoto et al., 22^(nd) National Meeting of American Chemical Society,American Chemical Scoiety: Washington, DC: Chicago, IL 2001; Kaneda etal, Soc. Neurosci. Abstr. 27:332.15 (2001); Niidome et al., Soc.Neurosci. Abstr. 27:332.14 (2001); and Suzuki et al., Bioorg. Med. Chem.Lett. 13:919-922 (2003). 54 E-2051 Kaneda, Soc. Neurosci. Abstr.28:490.1 (2002) 55

WO07110449 (see, e.g., Formulas I-XIII, the compounds described atParagraphs [0181]-[0183] and Examples 1-14, and claims 1- 72) 56

WO06040181 (see, e.g., Formulas I-X, the compounds described atParagraphs [0105]-[0109] and Examples 1-37, and in claims 1-56) 57

WO07118853 (see, e.g., Formulas I-XIII, the compounds described atParagraph [0320] and Examples 1-19, and the compounds of claims 1-165)58

WO07085357 (see, e.g., Formulas I-VII, the compounds described atParagraphs [0065]-[0067], Examples 1-6, and claims 1- 16) 59

WO07028638 (see, e.g., Formulas I-XXVI, the compounds described atParagraphs [0119]-[0123], Examples 1-24, and claims 1-20 60

WO07118854 (see, e.g., Formulas I-VII and the compounds of Examples 1-11and claims 1-36) 61

WO08008398 (see, e.g., Formulas I, I′, I″, II, and II′; Examples 1-377,and claims 1-7) 62

WO08150447 (see, e.g., Formulas I, I′, I″, and the compounds of Examples1- 135 and claims 1-5 63

Knutsen et al., Bioorg. Med. Chem. Lett. 17:662-667 (2007) 64

O'Neill, Brain Res. 888:138- 149 (2001); Hicks et al., Eur. J.Pharmacol. 408:241-248 (2000) 65

WO07084394 (see, e.g., the compounds of Formulas I and Ia-Ig, and thecompounds of Examples 1-11 and claims 1 and 2) 66

WO08066803 (see, e.g., Formulas I and II, the compound of Example 1, andclaims 1-11) 67

WO07075524 (see, e.g., Formulas (I), (Ia)-(Ie), the compounds ofExamples 1- 184, and claims 1-16) 68

WO08133867 (see, e.g., Formulas (I) and (II), the compounds of Examples1-163, and claims 1-16) 69

WO01045709 (see, e.g., Formula (1), the compounds of Example 4, andclaims 24- 38) WO06105670 (see, e.g., Formula (1), the compoundsdescribed at Paragraphs [0065] and [0066], and claims 1-13) 70

WO04089377 (see, e.g., Formula (1), Examples 1-5, original claims 1-13,and amended claims 1-17) 71

WO07071035 (see, e.g., Formula (1), the compounds of Examples 1-18, andclaims 20-35) 72

WO08043183 (see, e.g., Formulas (1) and (2), the compounds of Examples1-16, and claims 16-28) 73

WO04089922 (see, e.g., Formulas (1)-(4), the compounds of Examples 1-9,claims 1-17, and the compounds of Figure 1) 74

WO04105750 (see, e.g., Formulas (1)-(8), the compounds of Examples 1-10,claims 1-23, and Figure 1) 75

WO08031227 (see, e.g., Formulas (1) and (2), the compounds of Examples1-20, and claims 21-37) 76

Tatsumi et al., Jpn. J. Pharmacol. 73:193 (1997); Aoki et al., BrainRes. 890:162-169 (2001); Katsumata et al., Brain Res. 969:168-174(2003); Tamura et al., Brain Res. 890:170-176 (2001); Shi et al., J.Thorac. Cardiovasc. Surg. 129:364- 371 (2005); Small, IDrugs, 3:460-465(2000); Suma et al., Jpn. J. Pharmacol. 73:193 (1997); Shimidzu et al.,Naunyn Schmiedebergs Arch. Pharamcol. 355:601-608 (1997); and Suma etal., Eur. J. Pharmacol. 336:283-290 (1997). 77

Seko et al, Bioorg. Med. Chem. Lett. 11:2067-2070 (2001) 78

Seko et al., Bioorg. Med. Chem. 11:1901-1913 (2003). Seko et al.,Bioorg. Med. Chem. Lett. 12:915-918 (2002) 79

Seko et al., Bioorg. Med. Chem. Lett. 12:2267-2269 (2002) 80

Menzler et al., Bioorg. Med. Chem. Lett. 10:345-347 (2000) 81

Malone et al., 217^(th) National Meeting of the American ChemicalSociety, American Chemical Society: Washington DC: Anaheim CA 1999; Huet al., J. Med. Chem. 42:4239-4249 (1999) 82

Hu et al., Bioorg. Med. Chem. Lett. 9:907-912 (1999) 83

Hu et al., Bioorg. Med. Chem. Lett. 9:2151-2156 (1999) Ryder et al.,Bioorg. Med. Chem. Lett. 9:1813-1818 (1999) 84

Hu et al., Bioorg. Med. Chem. Lett. 9:1121-1126 (1999) 85

Bennett et al., Pain 33:87-107 (1988) 86

Hu et al., Bioorg. Med. Chem. 8:1203-1212 (2000) 87

Hu et al., Bioorg. Med. Chem. 8:1203-1212 (2000) 88

Hu et al., J. Med. Chem. 42:4239-4249 (1999) 89

Schelkun et al., Bioorg. Med. Chem. Lett. 9:2447-2452 (1999). 90

Yuen et al., Bioorg. Med. Chem. Lett. 8:2415-2418 (1998) 91

Song et al., J. Med. Chem. 43:3474-3477 (2000) 92

WO07125398 (see, e.g., Formula (I), the compounds of Examples 1-29, andclaims 1-9) 93

WO08124118 (see, e.g., Formula I-VI, the compounds of Paragraphs [0129]and Examples 1-5, and claims 1- 42) 94

Campbell et al., Eur. J. Pharmacol. 401:419-428 (2000) 95

Teodori et al., J. Med. Chem. 47:6070-6081 (2004) 96

Teodori et al., J. Med. Chem. 47:6070-6081 (2004) 97

Schroeder et al., Mol. Divers. 8:127-134 (2004). 98

WO06030211 (see, e.g., Formula (I), the compounds described at page 9,line 17- page 15, line 12, Examples 1- 99, and claims 1-12)

Farnesyl Amine Compounds

Compounds having a structure according to Formula (XI) can also be usedin the invention as calcium channel blockers.

where each R^(11A), R^(11B), and R^(11C) is selected, independently,from H or C₁₋₄ alkyl, and where 0, 1, 2, or 3 of the dashed bondsrepresents a carbon-carbon double bond (i.e., compounds of Formula (XI)can include 0, 1, 2, or 3 double bonds), provided that when 2 or 3carbon-carbon double bonds are present, the double bonds are notadjacent to one another. Compounds that include 0, 1, or 2 double bondscan be prepared according to methods known in the literature, e.g.,partial or total hydrogenation of the parent triene.

In some embodiments, compounds of Formula (XI) can be represented by thefollowing formula (XI-A),

where each R^(11A), R^(11B), R^(11C), and X is according to Formula(XI), and where each dashed bond represents an optional carbon-carbondouble bond.Still other farnesyl amine compounds can include those compounds thathave a structure according to Formula (XI-B),

where each R^(11A), R^(11B), R^(11C), and X is according to Formula(XI).

Exemplary compounds of Formula (XI) include

Cysteine-Derived Compounds

Amino acid derivatives, e.g., those described in U.S. Pat. No. 7,166,590or in Seko et al., Bioorg. Med. Chem. Lett. 11(16):2067-2070 (2001),each of which is herein incorporated by reference, can also be used inthe invention. For example, compounds having a structure according toFormula (XII) can be N-type calcium channel blockers.

wherein each of R^(12A), R^(12B), R^(12C), and R^(12D) is independently,selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl,C₇₋₁₄ alkaryl, C₃₋₄₀ alkcycloalkyl, and C₃₋₁₀ alkheterocyclyl; orR^(12A) and R^(12B) together complete a heterocyclic ring having atleast one nitrogen atom, n is an integer between 1-5, each of R^(12E)and R^(12F) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₇₋₁₄ alkaryl, C₃₋₁₀alkcycloalkyl, or C₃₋₁₀ alkheterocyclyl, and X is any pharmaceuticallyacceptable anion.

Exemplary compounds of Formula (XII) include

Flunarizine and Related Compounds

Still other compounds that can be used in the invention are chargedderivatives of flunarizine and related compounds (see, e.g., U.S. Pat.Nos. 2,883,271 and 3,773,939, as well as Zamponi et al., Bioorg. Med.Chem. Lett. 19: 6467 (2009)), each of which is hereby incorporated byreference. For example, compounds according to Formulas (XIII-A),(XIII-B), and (XIII-C) can be prepared according to, e.g., Zamponi etal., and used in the invention,

where each R^(13A)-R^(13J) and R^(13O)-R^(13T) is selected,independently, from H, halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C_(2A)alkynyl, C₂₋₄ heteroalkyl, C₇₋₁₄ alkaryl, C₃₋₁₀ alkcycloalkyl, and C₃₋₁₀alkheterocyclyl, OR^(13AA), NR^(13AB)R^(13AC), NR^(13AD)C(O)R^(13AE),S(O)R^(13AF), SO₂R^(13AG)R^(13AH), SO₂NR^(13AI)R^(13AJ), SO₃R^(13AK),CO₂R^(13AL), C(O)R^(13AM), and C(O)NR^(13AN)R^(13AO); and each ofR^(13AA)-R^(13AO is), independently, selected from H, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl;

each R^(13K), R^(13L), R^(13M), and R^(13N) is, independently, H or C₁₋₄alkyl, or R^(13K) and R^(13L), or R^(13M) and R^(13N), combine to formC═O, or R^(13K) and R^(13M) combine to form C═C;

R^(13Y) is H or C₁₋₄ alkyl;

R^(13Z) and R^(13Z′) are, independently, selected from H, halogen, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₇₋₁₄ alkaryl,C₃₋₁₀ alkcycloalkyl, and C₃₋₁₀ alkheterocyclyl; and

X⁻ is any pharmaceutically acceptable anion.

Exemplary compounds according to Formulas (XIII-A)-(XIII-C) include

Mibefradil Derivatives

Derivatives of mibrefradil, such as those described in U.S. Pat. No.4,808,605, hereby incorporated by reference can also be used. Exemplarymibrefadil derivatives include compounds of Formula (XIV),

where

n is an integer between 0-5;

R^(14A) is heterocyclyl (e.g., a heteroaryl such as benzimidazole),

each of R^(14B), R^(14C), R^(14D), and R1^(4E) is, independently, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₇₋₁₄ alkaryl,C₃₋₁₀ alkcycloalkyl, and C₃₋₁₀ alkheterocyclyl; and

R^(14F) is selected from H, halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₂₋₄ heteroalkyl, C₇₋₁₄ alkaryl, C₃₋₁₀ alkcycloalkyl, and C₃₋₁₀alkheterocyclyl, OR^(14G), NR^(14H)R^(14I), NR^(14J)C(O)R^(14K),S(O)R^(14L), SO₂R^(14M)R^(14N), SO₂NR^(14O)R^(14P), SO₃R^(14Q),CO₂R^(14R), C(O)R^(14S), and C(O)NR^(14T)R^(14V); and each ofR^(14G)-R^(13AO) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl.

An exemplary compound of Formula (XIV) is

4-Piperidinylaniline Compounds

Charged derivatives of 4-piperidinylaniline compounds (e.g., Compounds(86)-(88) of Table 2) can be prepared according to methods known in theliterature and described herein. For example, charged N-alkylderivatives (e.g., N-methyl) of Compounds (86)-(88) can be prepared andused in the compositions, methods, and kits described herein.

Still other channel blockers that can be quaternized or guanylatedaccording to the methods described herein are described, for example, inPCT Publication No. WO 2004/093813 (see, e.g., Tables 5, 6, and 8),which is herein incorporated by reference. For example, the channelblockers shown in Table 3 can be quaternized or guanylated as describedherein.

TABLE 3 No. Channel Blocker Exemplary References 105 Isradipine 106Nickel Chloride 107 A-53930A JP 08208690 108 AE-0047 Watanidipine EP00424901 dihydrochloride 109 AGN-190604 Inflammation, 19(2): 261-275(1995) 110 AGN-190744 EP372940 111 AH-1058 European Journal ofPharmacology, 398(1): 107-112 (2000) 112 AHR 5360C European Journal ofPharmacology 146(2-3): 215-22 (1988) 113 AHR 12234 ArchivesInternationales de Pharamcodynamie et de Therapie 301: 131-50 (1989) 114AHR-12742 ZA 08604522 115 AHR-16303B Journal of CardiovascularPharmacology 17(1): 134-44 (1991) 116 AHR-16462B Drug DevelopmentResearch, 22(3): 259-271 (1991) 117 AIT 110 118 AIT 111 119 AJ 2615 WO8601203 A1 120 AJ-3941 Arzneimittel Forschung 46(6): 567-71 (1996) 121(+)-alismol JP 04077420 A2 122 AM-336 (synthetic version of WO9954350CVID marine cone snail venom) 123 AM 543 124 amlodipine U.S. Pat. No.4,572,902 125 S-(−)amlodipine GB 2233974 A1 126 AN 132 EP 196648 127animpamil LU 42668 EP 64158 A1 128 antioquine (alkaloid from stemJournal of natural Products bark) 55(9): 1281-6 (1992) 129 AP-1067 IDDB268934 130 AQ-AH-208 CH 645628 A 131 AR 12456 (derivative of BE 902218A1 trapidil) Cardiovascular Drug Reviews 9(4): 385-397 (1991) 132aranidipine U.S. Pat. No. 4,446,325 133 atosiban EP 00112809 134azenidipine CS 905 EP 88266922 135 B 84439 EP 240828 136 barnidipine(derivative of U.S. Pat. No. 4,220,649 nicardipine) DE 02904552 137BAY-E-6927 DE 2117571 138 BAY-K-9320 EP 9206 139 BAY-T-7207 140 BBR-2160EP 28204 A2 141 BDF 8784 EP 25111 142 belfosdil/BMY 21891/SR7037 EP173041 A1 143 Bencylcalne/EGYT-201 FR 151193 144benipidine/KW3049/Nakadipine U.S. Pat. No. 4,448,964 145 bepridil U.S.Pat. No. 3,962,238 146 bisaramil/RGH 2957 WO 9622096 147 BK 129 Methodsand Findings in Experimental and Clinical Pharamcology 14(3): 175-81(1992) 148 BMS-181102 EP 559569 149 BMS-188107 U.S. Pat. No. 5,070,088150 BMY 20014 DE 3512995 A1 151 BMY 20064 DE 3512995 A1 152 BMY-43011Bioorganic and Medicinal Chemistry Letters, 3(12): 2817- 2820 (1993) 153BN 50149 WO 9323082 154 BN 50175 WO 9323082 155 BN 50394 WO 9323082 156BR 1022 Current Science 83(4): 426-431 (2002) 157 BRL 3287A WO 9323082158 BRL-32872 WO 09323024 159 buflomedil U.S. Pat. No. 4,326,083 160butoprozine DE 2707048 161 CAF 603 Organic and Bioorganic Chemistry, 22:3349: 52 (1994) 162 calciseptine (venom WO 2000 069900 polypeptide) 163calcium antagonists WO 9205165 164 calcium channel antagonists WO00236586 WO 0236567 165 calcium channel blocker (L- Journal of MedicinalChemistry, type) 39(15): 2922-2938 (1996) 166 calcium channel blockersEP 400665 A2 U.S. Pat. No. 4,965,356 167 calcium channel blockers WO9526325 168 carvedilol U.S. Pat. No. 4,503,067 169 caryachine BritishJournal of Pharmacology, 116(8): 3211-8 (1995) 170 CD-349 EP 92936 A1171 CD-832 EP 00370821 172 CER-2 metabolite of furnipidine WO 9919302173 cerebrocrast DE 3534385 174 CERM 11956 EP 138684 175 CERM-12816 IDDB283075 176 CGP 22442 WO 9323082 177 CGP 26797 WO 9323082 178 CGP 28727WO 9323082 179 CGP 32413 WO 9323082 180 changrolin Sci. Sin. (Engl. Ed.)22(10): 1220-8 (1979) 181 CHF-1521 (combination of delapril andmanidipine) 182 cilnidipine U.S. Pat. No. 4,672,068 183 cinnarizine U.S.Pat. No. 3,799,934 184 civamide WO 9640079 U.S. Pat. No. 5,840,762 185clentiazem/TA3090 EP 00127882 U.S. Pat. No. 4,567,175 186 clevidipine WO9512578 187 CNS-1067 IDdb 211675 188 CNS-1237 Annals of the New YorkAcademy of Sciences, 765 (Neuroprotective Agents): 210- 29 (1995) 189CNS-2103 (from spider venom) WO 9214709 A2 190 COR 28-22 WO 9323082 191COR 2707C WO 9323082 192 COR 3752C WO 9323082 193 CP-060S WO 9500471 A1194 CPC-301 IDdb 231888 195 CPC 304 IDdb 185705 196 CPC-317 IDdb 185700197 CPU 23 Yaoxue Xuebao, 25(11): 815-23 (1990) CAN 114: 143097 198CPU-86017 EP 00538844 199 CRE 202 WO 9323082 200 CRE 204 WO 9323082 201CRE 1005 WO 9323082 202 CRL-42752 WO 00003987 203 cronidipine (LF2-0254) EP 240398 A1 204 CV 159 FR 2511370 A1 205 D-2024 (verapamil(S))WO 09509150 206 D 2603 WO 9323082 207 dagapamil WO 9323082 EP 64158 A1208 darodipine PY108068 EP 00000150 209 dauricine NSC 36413 ActaPharmacologica Sinica 7(6): 543-7 (1986) 210 desmethyl verapamil 211 DHM9 WO 8604581 A1 212 DHP 218/PAK 9 EP 00121117 213 diclofurime DE79-29227999 214 dihydropyridine calcium Journal of Medicinal Chemistrychannel blockers 41(4): 509-514 (1998) 215 diltiazem U.S. Pat. No.3,562,257 216 diperdipine EP 00218996 217 dipfluzine DE 3318577 A1 218diproteverine BRL 40015 BE 866208 219 dopropidil EP 00031771 220dotarizine/FI 6026 U.S. Pat. No. 4,883,797 221 DTZ-323 MolecularPharmacology, 51(2): 262-268 (1997) 222 E-2050 JP 2001199949 A2 223 E4080 EP 344577 A2 224 efonidipine hydrochloride U.S. Pat. No. 4,885,284225 EG 1088 EP 56637 A1 226 EGIS 3966 DE 4027052 A1 227 eglodipine DE3825962 A1 228 emopamil (racemic) SZ 45 DE 3344755 A1 229 (S)-emopamilDE 3344755 A1 230 enalapril_nitrendipine, Vita- EP 00884054 Inveest 231etafenonee LG 11457 DE 1265758 232 ethosuximide 233 eugenodilol JP11255719 A2 234 evodiamine JP 52077098 235 F-0401 EP 00320984 236falipamil AQA 39 Journal of Medicinal Chemistry, 33(5): 1496-504 (1990)237 fantofarone SR 33557 EP 235111 A1 U.S. Pat. No. 4,957,925 238fasudil (iv formulation), Asahi U.S. Pat. No. 4,678,783 239 FCE-24265 EP373645 A1 240 FCE-26262 241 FCE-27335 242 FCE-27892 243 FCE-28718 EP00755931 244 fedopamil 245 felodipine U.S. Pat. No. 4,264,611 246felodipine + ramipril WO 09607400 (Astra/Aventis) 247 fendiline U.S.Pat. No. 3,262,977 248 feniline 249 flezelastine, D 18024 EP 590551 A2250 flordipine 251 fluodipine U.S. Pat. No. 3773939 252 fluphenazine,S94 Journal of Medicinal Chemistry, SQ 4918 19(6): 850-2 (1976)Triflumethazine Vespazine 253 fostedil KB944 EP 10120 254 FPL 62129 EP125803 A2 255 FR46171 256 FR-172516 JP 09040647 257 FRC 9411 258 FRG8653 259 FRG-8701 260 furaldipine 261 furnidipine (CRE 319) Journal ofMedicinal Chemistry, 38(15): 2830-41 (1995) 262 GOE 5057 263 GOE 5584 AEP 173933 A1 264 GOE 93007 265 GR 60139 266 GR 55234A (R-enantiomer ofHaemotalogica, 79(4): 328-33 telupidine) (1994) 267 GR 55235A(L-enantiomer of Haemotalogica, 79(4): 328-33 telupidine) (1994) 268GS-386 269 GYKI 46544 270 H32438 271 HA 22 U.S. Pat. No. 5,240,947 272HA 23 U.S. Pat. No. 5,240,947 273 HA 1004 274 GA 1077 275 HE 30346 276HNS 32 JP 08311007 A2 277 HOE 166 Molecular Pharmacology 33(4): 363-9(1988) 278 HOE 263 279 HP 406 U.S. Pat. No. 4,521,537 280 ICI 206970 EP293170 A1 19881130 281 iganidipine JP 63225355 A2 19880920 282 IHC 72Acta Pharmaceutica Sinica, 27(6): 407-11 (1992) 283 ipenoxazone 284isradipine U.S. Pat. No. 4,466,972 285 JTV-519 WO 09212148 286 KB 2796287 KP-840 Yakubutsu, Seishin, Kodo, 12(6): 353 (1992) 288 KP 873 289KT-362 Archiv Der Pharmazie, 328(4): 313-6 (1995) 290 KT 2230 GeneralPharmacology, 22(3): 443-8 (1991) 291 KW 3049 (see benipidine) 292L-366682 EP 00444898 293 L-651582 294 L 735821 WO 9514471 A1 19950601British Journal of Pharmacology, 132(1): 101-110 (2001) 295 lacidipineGR 43659 Sn305 U.S. Pat. No. 4,801,599 DE 03529997 296 LAS 30356 297 LAS30398 298 LAS 30538 Journal of Pharmacy and Pharmacology, 44(10: 830-5(1992) 299 LAS Z077 300 LCB-2514 301 lemildipine P 59152373 A2 302lercanidipine U.S. Pat. No. 4,705,797 303 leualacin EP 00358418 304levosemotiadil SA 3212 WO 08700838 305 lidoflazine R7904 U.S. Pat. No.3,267,104 306 lifarizine RS 87476 U.S. Pat. No. 0,435,417 307 LOE-908308 lomerizine KB 2796 U.S. Pat. No. 4,663,325 EP 00158566 309 LU 49700(main metabolite of DE 3642331 A1 gallopamil) 310 LU 49938 311 LY-042826European Journal of Pharmacology, 408(3): 241-248 (2000) 312 LY-393615European Journal of Pharmacology, 408(3): 241-248 (2000) 313manidipine/CV U.S. Pat. No. 4,892,875 4093/franidipine EP 00094159 314MCI 176 (MY7674) EP 169537 A2 315 McN 5691 (see RWJ 26240) 316 McN-6186317 MCN 6497 318 MD 260792 319 MDL 143 320 MDL 12330A 321 MDL 16582A WO9323082 322 MDL 72567 GB 2137622 A1 19841010 CAN 102: 95548 323 MEM1003/nimopidine analog/BAY Z 4406 324 mepirodipine 325 mesudipine 326mibefradil EP 00268148 U.S. Pat. No. 4,808,605 327 minodipine 328mioflazine 329 MJ 14712 330 monatepil maleate (AD 2615) WO 08601203 U.S.Pat. No. 4,749,703 331 MPC 1304 332 MPC 2101 FR 2514761 A1 333 MR-14134Pharmacology, 51(2): 84-95 (1995) 334 N-3601 EP 254322 A1 335 N 20776336 N-allyl secoboldine 337 naltiazem Ro 23-6152 U.S. Pat. No. 4,652,561338 NB 818 339 NC 1100 340 NC O 700 341 NCC 09-0026 342 nexopamil EP00271013 343 NH 2250 344 NH 2716 345 nicainoprol RU 42924 DE 2934609 346nicardipine (nifelan) U.S. Pat. No. 3,985,847 347 nictiazem 348nifedipine U.S. Pat. No. 3,485,847 349 nigulipine WO 8807525 A1 350niludipine 351 nilvadipine FK 235 U.S. Pat. No. 4,338,322 DE 02940833352 nimodipine U.S. Pat. No. 3,842,096 353 misoldipine Bay y 5552 U.S.Pat. No. 4,154,839 354 nitrendipine Bay k 5009 U.S. Pat. No. 3,799,934355 NMDA/calcium channel WO 09745115 antagonists, Allelix 356 NKY 722357 NMED 126 (MC-34D) WO 0145709 A1 U.S. Pat. No. 6,387,897 358 NMED 427WO 0145709 A1 U.S. Pat. No. 6,387,897 359 NMED 724 WO 0145709 A1 U.S.Pat. No. 6,387,897 360 NMED 826 WO 0145709 A1 U.S. Pat. No. 6,387,897361 NMED JM-G-10 WO 0145709 A1 U.S. Pat. No. 6,387,897 362 NMED 15739-1B4 WO 0145709 A1 U.S. Pat. No. 6,387,897 363 NMED 160 39-45-3 WO0145709 A1 U.S. Pat. No. 6,387,897 364 NNC-09-0026 WO 9201672 365 NP 252Life Sciences, 48(2): 183-8 (1991) 366 NS 626 367 NS-638 U.S. Pat. No.5,314,903 EP 545845 A1 368 NS-649 EP 520200 A2 369 NS-696 370 NS-7 WO09607641 371 NS 3034 372 NZ 105 373 olradipine S 11568 FR 2602231 A1 374ONO-2921 WO 0000470 A1 375 OPC 13340 376 OPC 88117 EP 236140 A2 377 ORG13020 378 Org-13061 Fundamental & Clinical Pharmacology, 11(5): 416-426(1997) 379 OSAT (nifedipine) 380 osthole JP 47000430 381 oxodipine IQB837V ES 531033 A1 382 P 0825 383 P 1268 384 palonidipine hydrochlorideEp 128010 A2 385 PCA-50922 386 PCA-50938 Brain Research 772(1,2): 57-62(1997) 387 PCA-50941 388 PCA 50982 389 PD-0204318 WO 9943658 A1 390PD-029361 IDdb 300520 391 PD 122860 Ep 206747 A2 392 PD 151307 U.S. Pat.No. 6,423,689 J. Med. Chem. 43: 3472 (2000) 393 PD-157667 U.S. Pat. No.5,767,129 394 PD-158143 WO 9705125 A1 395 PD 173212 396 PD 175069 WO9854123 A1 397 PD 176078 WO 9955688 J. Med. Chem. 43: 3474 (2000) 398 PD181283 Bioorganic & Medicinal Chemistry Letters, 9(16): 2453- 2458(1999) 399 pelanserin 400 perhexiline GB 1025578 401 petrosynolTetrahedron, 49(45): 10435-8 (1993) 402 PF 244 403 PFS 1144 (EO 122) DE2802208 404 pirmenol U.S. Pat. No. 4,112,103 405 pirprofurol 406 407PN200110 408 PNU 156654E WO 9705102 A1 409 pranidipine EP 00145434 410prenylamine 411 propiverine DD 106643 412 ptilomycalin AM 413 QM 96233414 QM 96159 415 QM 96127 416 QX-314 Biophysical Journal, 27(1): 39- 55(1979) 417 R 56865 EP 184257 A1 418 R 59494 Ep 184257 A1 419 R71811 420Rec 152288 421 Rec 152375, Rec 15/375 422 RGH-2716 (TDN 345) EP 414421A2 423 RGH 2970 424 riodipine 425 Ro-11-2933 EP 00523493 426 Ro 18-3981427 Ro 40-5967 428 RO 445912 dithiane derivatives BiochemicalPharmacology, of tiapamil 50(2): 187-96 (1995) 429 ronipamil 430 RS-5773EP 00353032 431 RS 93007 432 RS 93522 U.S. Pat. No. 4,595,690 433RU-43945 WO 9323082 A1 434 RWJ-22108 U.S. Pat. No. 04,845,225 435RWJ-22726 U.S. Pat. No. 04,845,225 436 RWJ 26240 McN 5691 EP 146721 A2437 RWJ 26899 EP 237191 A1 438 RJW-26902 439 RWJ-29009 EP 00493048 440RWJ-37868 WO 0048584 441 ryanodine 442 S-(−)-amlodipine 443 S 11568 444S 12967 ZA 9000231 A 445 S-12968 EP 00406502 446 S-2150 Ep 00615971 447S-312-d JP 03052890 448 S 830327 449 SA 2572 JP 63104969 A2 450 SA 2995451 SA 3212 452 sabeluzole Ep 184257 A1 453 safinamide EP 400495 A1 454sagandipine 455 salicylaldoxime Clinical and Experimental Pharmacologyand Physiology 26(12): 964-9 (1999) 456 SANK-71996 457 SB-201823A WO09202502 458 SB-206284A 459 SB 221420A WO 9002494 A1 460 SB-237376 WO0209761 A2 461 SB 262470 WO 0183546 A1 462 SC 30552 463 SDZ-249482 464selodipine 465 semotiadil (SD 3211) U.S. Pat. No. 4,786,635 JP 09012576466 SIM 6080 Ep 293925 A2 467 sipatrigine EP 372934 A2 468 sinomenine(active from a WO 0269971 A1 Chinese medicinal plant) 469 siratiazem WO09117153 470 SKF-45675 471 SKF-96365 European Journal of Pharmacology188(6): 417-21 (1990) 472 SKT-M-26 473 SL-34.0829 WO 0209761 A2 474 SL651708 475 SL 851016 476 SL-870495 477 SM-6586 EP 00177965 478 SNX-124479 SNX 185 WO 9310145 A1 480 SNX-236 WO 09313128 481 SNX-239 Pain,60(1): 83-90 (1995) 482 SNX-483 (peptides from WO 9805780 A2 tarantulavenom) 483 sornidipine 484 SQ 31486 EP 205334 A2 485 SQ 31727 486 SQ31765 487 SQ 32321 488 SQ 32324 489 SQ 32547 EP 400665 A2 490 SQ 32926EP 400665 A2 491 SQ-33351 WO 09006118 492 SQ 33537 493 SQ 34399 494SR-33805 EP 576347 A1 495 SUN 5647 496 SUN 6087 497 SUN-N8075 WO 9923072A2 498 T-477 EP 00441539 499 TA-993 JP 01050872 500 taludipine 501tamolarizine EP 00354068 502 TDN-345 503 Teczem 504 temiverine CAN 131:193592 505 terflavoxate EP 72620 A1 506 terodiline TD 758 U.S. Pat. No.3,371,014 507 tetrandrine Clinical and Experimental Pharmacology andPhysiology, 23(8): 715-753 (1996) 508 TH-1177 509 TH-9229 WO 09607415510 thapsigargin British Journal of Pharmacology, 95(3): 705-712 (1985)511 tiapamil 512 tinctormine Chemical & Pharmaceutical Bulletin 40(12):3355-7 (1992) 513 TJN 220 (O-ethylfangchinoline) JP 63179878 A2 514 TMB8 Journal of Cell Science 79: 151- 160 (1985) 515 TN-871 EuropeanJournal of Pharmacology 342 (2/3): 167- 175 (1998) 516 TR 2957 517trapidil 518 trimetazidine U.S. Pat. No. 3,262,852 519 TY-10835Pharmacometrics, 1998, 54: 3 (153) 520 U-88999 WO 9204338 521 U-92032 WO09204338 522 U-92798 WO 9204338 A1 523 UK 1745 EP 653426 A1 524 UK-51656EP 00089167 525 UK 52831 JP 59118782 A2 526 UK 55444 EP 00132375 527 UK56593 528 UK-84149 EP 404359 A1 529 ULAH 99 European Journal ofPharmacology, 229(1): 55-62 (1992) 530 vantanipidine EP 257616 A2 531verapamil, verelan U.S. Pat. No. 3,261,859 532 S-verapamil, D-2024,levoverapamil WO 09509150 533 vexibinol Sophoraflavanone G Chemical andPharmaceutical Bulletin 38(4): 1039-44 (1990) 534 vinigrol 535vintoperol RGH 2981 RT 303 WO 9207851 536 vingrol 537 vintoperol/RGH2981/RT 303 WO 9207851 538 VUF-8929 EP 467435 A2 539 VULM 993 540vantanipidine Ep 257616 A2 541 W 787 542 WAS 4206 543 WK 269 544 WY27569 545 WY 44644 546 WY 44705 547 WY 46622 548 WY 47324 549xanthonolol U.S. Pat. No. 5,495,005 550 Y 19638 551 Y-22516 WO 9323082552 Y 208835 553 YC 114 554 YH-334 EP 00366548 555 YM 15430-1 (see YM430) 556 YM-16151-4 (YM 151) EP 00167371 557 YM-430 (YM 15430) WO0209761 A2 558 YS 035 BE 897244 559 YS 161 560 Z-6568 Journal of MassSpectrometry, 31(1): 37-46 (1996) 561 ziconotiide omega WO 9107980conotoxin/MVIIA/SNX-111 562 ZM-224832 EP 00343865 563 zonisamide U.S.Pat. No. 4,172,896

Synthesis

The synthesis of charge-modified ion channel blockers may involve theselective protection and deprotection of alcohols, amines, ketones,sulfhydryls or carboxyl functional groups of the parent ion channelblocker, the linker, the bulky group, and/or the charged group. Forexample, commonly used protecting groups for amines include carbamates,such as tert-butyl, benzyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl,9-fluorenylmethyl, allyl, and m-nitrophenyl. Other commonly usedprotecting groups for amines include amides, such as formamides,acetamides, trifluoroacetamides, sulfonamides, trifluoromethanesulfonylamides, trimethylsilylethanesulfonamides, and tert-butylsulfonyl amides.Examples of commonly used protecting groups for carboxyls includeesters, such as methyl, ethyl, tert-butyl, 9-fluorenylmethyl,2-(trimethylsilyl)ethoxy methyl, benzyl, diphenylmethyl, O-nitrobenzyl,ortho-esters, and halo-esters. Examples of commonly used protectinggroups for alcohols include ethers, such as methyl, methoxymethyl,methoxyethoxymethyl, methylthiomethyl, benzyloxymethyl,tetrahydropyranyl, ethoxyethyl, benzyl, 2-napthylmethyl, O-nitrobenzyl,P-nitrobenzyl, P-methoxybenzyl, 9-phenylxanthyl, trityl (includingmethoxy-trityls), and silyl ethers. Examples of commonly used protectinggroups for sulfhydryls include many of the same protecting groups usedfor hydroxyls. In addition, sulfhydryls can be protected in a reducedform (e.g., as disulfides) or an oxidized form (e.g., as sulfonic acids,sulfonic esters, or sulfonic amides). Protecting groups can be chosensuch that selective conditions (e.g., acidic conditions, basicconditions, catalysis by a nucleophile, catalysis by a Lewis acid, orhydrogenation) are required to remove each, exclusive of otherprotecting groups in a molecule. The conditions required for theaddition of protecting groups to amine, alcohol, sulfhydryl, andcarboxyl functionalities and the conditions required for their removalare provided in detail in T. W. Green and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis (2^(nd) Ed.), John Wiley & Sons, 1991 and P.J. Kocienski, Protecting Groups, Georg Thieme Verlag, 1994.

Charge-modified ion channel blockers can be prepared using techniquesfamiliar to those skilled in the art. The modifications can be made, forexample, by alkylation of the parent ion channel blocker using thetechniques described by J. March, Advanced Organic Chemistry: Reactions,Mechanisms and Structure, John Wiley & Sons, Inc., 1992, page 617. Theconversion of amino groups to guanidine groups can be accomplished usingstandard synthetic protocols. For example, Mosher has described ageneral method for preparing mono-substituted guanidines by reaction ofaminoiminomethanesulfonic acid with amines (Kim et al., TetrahedronLett. 29:3183 (1988)). A more convenient method for guanylation ofprimary and secondary amines was developed by Bernatowicz employing1H-pyrazole-1-carboxamidine hydrochloride;1-H-pyrazole-1-(N,N′-his(tert-butoxycarbonyl)carboxamidine; or1-II-pyrazole-1-(N,N′-bis(benzyloxycarbonyl)carboxamidine. Thesereagents react with amines to give mono-substituted guanidines (seeBernatowicz et al., J. Org. Chem. 57:2497 (1992); and Bernatowicz etal., Tetrahedron Lett. 34:3389 (1993)). In addition, thioureas andS-alkyl-isothioureas have been shown to be useful intermediates in thesyntheses of substituted guanidines (Poss et al., Tetrahedron Lett.33:5933 (1992)). In certain embodiments, the guanidine is part of aheterocyclic ring having two nitrogen atoms (see, for example, thestructures below).

The ring system can include an alkylene or

alkenylene of from 2 to 4 carbon atoms, e.g., ring systems of 5, 6, and7-membered rings. Such ring systems can be prepared, for example, usingthe methods disclosed by Schlama et al., J. Org. Chem. 62:4200 (1997).

Charge-modified ion channel blockers can be prepared by alkylation of anamine nitrogen in the parent compound as shown in Scheme 1.

Alternatively, charge-modified ion channel blockers can be prepared byintroduction of a guanidine group. The parent compound can be reactedwith a cynamide, e.g., methylcyanamide, as shown in Scheme 2 orpyrazole-1-carboxamidine derivatives as shown in Scheme 3 where Z is Hor a suitable protecting group. Alternatively, the parent compound canbe reacted with cyanogens bromide followed by reaction withmethylchloroaluminum amide as shown in Scheme 4. Reagents such as2-(methylthio)-2-imidazoline can also be used to prepare suitablyfunctionalized derivatives (Scheme 5).

Any ion channel blocker containing an amine nitrogen atom (e.g., acompound selected from Compounds (1)-(563) or a compound according toFormulas (I)-(XIV)) can be modified as shown in Schemes 1-5.

TRPV1 Agonists

TRPV1 agonists that can be employed in the methods and kits of theinvention include but are not limited to any that activates TRPV1receptors on nociceptors and allows for entry of at least one inhibitorof voltage-gated ion channels. A suitable TRPV1 agonist is capsaicin oranother capsaicinoids, which are members of the vanilloid family ofmolecules. Naturally occurring capsaicinoids are capsaicin itself,dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin,homocapsaicin, and nonivamide, whose structures are provided below.

Other suitable capsaicinoids and capsaicinoid analogs and derivativesfor use in the compositions and methods of the present invention includenaturally occurring and synthetic capsaicin derivatives and analogsincluding, e.g., vanilloids (e.g., N-vanillyl-alkanedienamides,N-vanillyl-alkanedienyls, and N-vanillyl-cis-monounsaturatedalkenamides), capsiate, dihydrocapsiate, nordihydrocapsiate and othercapsinoids, capsiconiate, dihydrocapsiconiate and other coniferylesters, capsiconinoid, resiniferatoxin, tinyatoxin, civamide,N-phenylmethylalkenamide capsaicin derivatives, olvanil,N-[(4-(2-aminoethoxy)-3-methoxyphenyl)methyl]-9Z-octa-decanamide,N-oleyl-homovanillamide, triprenyl phenols (e.g., scutigeral),gingerols, piperines, shogaols, guaiacol, eugenol, zingerone, nuvanil,NE-19550, NE-21610, and NE-28345. Additional capsaicinoids, theirstructures, and methods of their manufacture are described in U.S. Pat.Nos. 7,446,226 and 7,429,673, which are hereby incorporated byreference.

Additional suitable TRPV1 agonists include but are not limited toeugenol, arvanil (N-arachidonoylvanillamine), anandamide,2-aminoethoxydiphenyl borate (2APB), AM404, resiniferatoxin, phorbol12-phenylacetate 13-acetate 20-homovanillate (PPAHV), olvanil (NE19550), OLDA (N-oleoyldopamine), N-arachidonyldopamine (NADA),6′-iodoresiniferatoxin (6′-IRTX), C18 N-acylethanolamines, lipoxygenasederivatives such as 12-hydroperoxycicosatetraenoic acid, inhibitorcysteine knot (ICK) peptides (vanillotoxins), piperine, MSK195(N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-2-[4-(2-aminoethoxy)-3-methoxyphenyl]acetamide),JYL79(N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-N′-(4-hydroxy-3-methoxybenzyl)thiourea),hydroxy-alpha-sanshool, 2-aminoethoxydiphenyl borate, 10-shogaol,oleylgingerol, oleylshogaol, and SU200(N-(4-tert-butylbenzyl)-N′-(4-hydroxy-3-methoxybenzyl)thiourea).

Still other TRPV1 agonists include amylocaine, articaine, benzocaine,bupivacaine, carbocaine, carticaine, chloroprocaine, cyclomethycaine,dibucaine (cinchocaine), dimethocaine (larocaine), etidocaine,hexylcaine, levobupivacaine, lidocaine, mepivacaine, meprylcaine(oracaine), metabutoxycaine, piperocaine, prilocaine, procaine(novacaine), proparacaine, propoxycaine, risocaine, ropivacaine,tetracaine (amethocaine), and trimecaine.

TRP1A Agonists

TRP1A agonists that can be employed in the methods and kits of theinvention include any that activates TRP1A receptors on nociceptors orpruriceptors and allows for entry of at least one inhibitor ofvoltage-gated ion channels. Suitable TRP1A agonists include but are notlimited to cinnamaldehyde, allyl-isothiocynanate, diallyl disulfide,icilin, cinnamon oil, wintergreen oil, clove oil, acrolein,hydroxy-alpha-sanshool, 2-aminoethoxydiphenyl borate, 4-hydroxynonenal,methyl p-hydroxybenzoate, mustard oil, and 3′-carbamoylbiphenyl-3-ylcyclohexylcarbamate (URB597). Still other agonists include amylocaine,articaine, benzocaine, bupivacaine, carbocaine, carticaine,chloroprocaine, cyclomethycaine, dibucaine (cinchocaine), dimethocaine(larocaine), etidocaine, hexylcaine, levobupivacaine, lidocaine,mepivacaine, meprylcaine (oracaine), metabutoxycaine, piperocaine,prilocaine, procaine (novacaine), proparacaine, propoxycaine, risocaine,ropivacaine, tetracaine (amethocaine), and trimecaine.

P2X Agonists

P2X agonists that can be employed in the methods and kits of theinvention include any that activates P2X receptors on nociceptors orpruriceptors and allows for entry of at least one inhibitor ofvoltage-gated ion channels. Suitable P2X agonists include but are notlimited to 2-methylthio-ATP, 2′ and 3′-O-(4-benzoylbenzoyl)-ATP, andATP5′-O-(3-thiotriphosphate).

TRPM8 Agonists

TRPM8 agonists that can be employed in the methods and kits of theinvention include any that activates TRPM8 receptors on nociceptors orpruriceptors and allows for entry of at least one inhibitor ofvoltage-gated ion channels. Suitable TRPM8 agonists include but are notlimited to menthol, iciclin, eucalyptol, linalool, geraniol, andhydroxycitronellal.

Additional Agents

If desired, one or more additional biologically active agents typicallyused to treat neurogenic inflammation may be used in combination with acomposition of the invention described herein. The biologically activeagents include, but are not limited to, acetaminophen, NSAIDs,glucocorticoids, narcotics (e.g. opioids), tricyclic antidepressants,amine transporter inhibitors, anticonvulsants, antiproliferative agents,and immune modulators. The biologically active agents can beadministered prior to, concurrent with, or following administration of acomposition of the invention, using any formulation, dosing, oradministration known in the art that is therapeutically effective.

Non-steroidal anti-inflammatory drugs (NSAIDs) that can be administeredto a patient (e.g., a human) suffering from neurogenic inflammation incombination with a composition of the invention include, but are notlimited to, acetylsalicylic acid, amoxiprin, benorylate, benorilate,choline magnesium salicylate, diflunisal, ethenzamide, faislamine,methyl salicylate, magnesium salicylate, salicyl salicylate,salicylamide, diclofenac, aceclofenac, acemethacin, alclofenac,bromfenac, etodolac, indometacin, nabumetone, oxametacin, proglumetacin,sulindac, tolmetin, ibuprofen, alminoprofen, benoxaprofen, carprofen,dexibuprofen, dexketoprofen, fenbufen, fenoprofen, flunoxaprofen,flurbiprofen, ibuproxam, indoprofen, ketoprofen, ketorolac, loxoprofen,naproxen, oxaprozin, pirprofen, suprofen, tiaprofenic acid, mefenamicacid, flufenamic acid, meclofenamic acid, tolfenamic acid,phenylbutazone, ampyrone, azapropazone, clofezone, kebuzone, metamizole,mofebutazone, oxyphenbutazone, phenazone, sulfinpyrazone, piroxicam,droxicam, lornoxicam, meloxicam, tenoxicam, and the COX-2 inhibitorscelecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib,and pharmaceutically acceptable salts thereof.

Glucocorticoids that can be administered to a patient (e.g., a human)suffering from neurogenic inflammation in combination with a compositionof the invention include, but are not limited to, hydrocortisone,cortisone acetate, prednisone, prednisolone, methylprednisolone,dexamethasone, betamethasone, triamcinolone, beclometasone,fludrocortisones acetate, deoxycorticosterone acetate, aldosterone, andpharmaceutically acceptable salts thereof.

Narcotics that can be administered to a patient (e.g., a human)suffering from neurogenic inflammation in combination with a compositionof the invention include, but are not limited, to tramadol, hydrocodone,oxycodone, morphine, and pharmaceutically acceptable salts thereof.

Antiproliferative and immune modulatory agents that can be administeredto a patient (e.g., a human) suffering from neurogenic inflammation incombination with a composition of the invention include, but are notlimited to, alkylating agents, platinum agents, antimetabolites,topoisomerase inhibitors, dihydrofolate reductase inhibitors, antitumorantibiotics, antimitotic agents, aromatase inhibitors, thymidylatesynthase inhibitors, DNA antagonists, farnesyltransferase inhibitors,pump inhibitors, histone acetyltransferase inhibitors, metalloproteinaseinhibitors, ribonucleoside reductase inhibitors, TNF-alpha agonists,TNF-alpha antagonists or scavengers, interleukin 1 (IL-1) antagonists orscavengers, endothelin A receptor antagonists, retinoic acid receptoragonists, hormonal agents, antihormonal agents, photodynamic agents, andtyrosine kinase inhibitors.

Formulation of Compositions

The administration of a combination of the invention may be by anysuitable means that results in the reduction of inflammation at thetarget region (e.g., any inflamed tissue or mucosal surface). Theinhibitor(s) of voltage-gated ion channels may be contained in anyappropriate amount in any suitable carrier substance, and are generallypresent in amounts totaling 1-95% by weight of the total weight of thecomposition. The composition may be provided in a dosage form that issuitable for intraarticular, oral, parenteral (e.g., intravenous,intramuscular), rectal, cutaneous, subcutaneous, topical, transdermal,sublingual, nasal, vaginal, intravesicular, intraurethral, intrathecal,epidural, aural, or ocular administration, or by injection, inhalation,or direct contact with the nasal, genitourinary, gastrointestinal,reproductive or oral mucosa.

Thus, the composition may be in the form of, e.g., tablets, capsules,pills, powders, granulates, suspensions, emulsions, solutions, gelsincluding hydrogels, pastes, ointments, creams, plasters, drenches,osmotic delivery devices, suppositories, enemas, injectables, implants,sprays, preparations suitable for iontophoretic delivery, or aerosols.The compositions may be formulated according to conventionalpharmaceutical practice (see, e.g., Remington: The Science and Practiceof Pharmacy, 20th edition, 2000, ed. A. R. Gennaro, Lippincott Williams& Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology,eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).

Each compound of a combination therapy, as described herein, may beformulated in a variety of ways that are known in the art. For example,the first and second agents of the combination therapy may be formulatedtogether or separately. Desirably, the first and second agents areformulated together for the simultaneous or near simultaneousadministration of the agents.

The individually or separately formulated agents can be packagedtogether as a kit. Non-limiting examples include, but are not limitedto, kits that contain, e.g., two pills, a pill and a powder, asuppository and a liquid in a vial, two topical creams, etc. The kit caninclude optional components that aid in the administration of the unitdose to patients, such as vials for reconstituting powder forms,syringes for injection, customized IV delivery systems, inhalers, etc.Additionally, the unit dose kit can contain instructions for preparationand administration of the compositions.

The kit may be manufactured as a single use unit dose for one patient,multiple uses for a particular patient (at a constant dose or in whichthe individual compounds may vary in potency as therapy progresses); orthe kit may contain multiple doses suitable for administration tomultiple patients (“bulk packaging”). The kit components may beassembled in cartons, blister packs, bottles, tubes, and the like.

Controlled Release Formulations

Each compound of the invention, alone or in combination with one or moreof the biologically active agents as described herein, can be formulatedfor controlled release (e.g., sustained or measured) administration, asdescribed in U.S. Patent Application Publication Nos. 2003/0152637 and2005/0025765, each incorporated herein by reference. For example, acompound of the invention, alone or in combination with one or more ofthe biologically active agents as described herein, can be incorporatedinto a capsule or tablet, that is administered to the site ofinflammation.

Any pharmaceutically acceptable vehicle or formulation suitable forlocal infiltration or injection into a site to be treated (e.g., apainful surgical incision, wound, or joint), that is able to provide asustained release of compound of the invention, alone or in combinationwith one or more of the biologically active agents as described herein,may be employed to provide for prolonged elimination or alleviation ofinflammation, as needed. Slow release formulations known in the artinclude specially coated pellets, polymer formulations or matrices forsurgical insertion or as sustained release microparticles, e.g.,microspheres or microcapsules, for implantation, insertion, infusion orinjection, wherein the slow release of the active medicament is broughtabout through sustained or controlled diffusion out of the matrix and/orselective breakdown of the coating of the preparation or selectivebreakdown of a polymer matrix. Other formulations or vehicles forsustained or immediate delivery of an agent to a preferred localizedsite in a patient include, e.g., suspensions, emulsions, gels, liposomesand any other suitable art known delivery vehicle or formulationacceptable for subcutaneous or intramuscular administration.

A wide variety of biocompatible materials may be utilized as acontrolled release carrier to provide the controlled release of acompound of the invention, alone or in combination with one or morebiologically active agents, as described herein. Any pharmaceuticallyacceptable biocompatible polymer known to those skilled in the art maybe utilized. It is preferred that the biocompatible controlled releasematerial degrade in vivo within about one year, preferably within about3 months, more preferably within about two months. More preferably, thecontrolled release material will degrade significantly within one tothree months, with at least 50% of the material degrading into non-toxicresidues, which are removed by the body, and 100% of the compound of theinvention being released within a time period within about two weeks,preferably within about 2 days to about 7 days. A degradable controlledrelease material should preferably degrade by hydrolysis, either bysurface erosion or bulk erosion, so that release is not only sustainedbut also provides desirable release rates. However, the pharmacokineticrelease profile of these formulations may be first order, zero order,bi- or multi-phasic, to provide the desired reversible local anestheticeffect over the desired time period.

Suitable biocompatible polymers can be utilized as the controlledrelease material. The polymeric material may comprise biocompatible,biodegradable polymers, and in certain preferred embodiments ispreferably a copolymer of lactic and glycolic acid. Preferred controlledrelease materials which are useful in the formulations of the inventioninclude the polyanhydrides, polyesters, co-polymers of lactic acid andglycolic acid (preferably wherein the weight ratio of lactic acid toglycolic acid is no more than 4:1 i.e., 80% or less lactic acid to 20%or more glycolic acid by weight)) and polyorthoesters containing acatalyst or degradation enhancing compound, for example, containing atleast 1% by weight anhydride catalyst such as maleic anhydride. Examplesof polyesters include polylactic acid, polyglycolic acid and polylacticacid-polyglycolic acid copolymers. Other useful polymers include proteinpolymers such as collagen, gelatin, fibrin and fibrinogen andpolysaccharides such as hyaluronic acid.

The polymeric material may be prepared by any method known to thoseskilled in the art. For example, where the polymeric material iscomprised of a copolymer of lactic and glycolic acid, this copolymer maybe prepared by the procedure set forth in U.S. Pat. No. 4,293,539,incorporated herein by reference. Alternatively, copolymers of lacticand glycolic acid may be prepared by any other procedure known to thoseskilled in the art. Other useful polymers include polylactides,polyglycolides, polyanhydrides, polyorthoesters, polycaprolactones,polyphosphazenes, polyphosphoesters, polysaccharides, proteinaceouspolymers, soluble derivatives of polysaccharides, soluble derivatives ofproteinaceous polymers, polypeptides, polyesters, and polyorthoesters ormixtures or blends of any of these. Pharmaceutically acceptablepolyanhydrides which are useful in the present invention have awater-labile anhydride linkage. The rate of drug release can becontrolled by the particular polyanhydride polymer utilized and itsmolecular weight. The polysaccharides may be poly-1,4-glucans, e.g.,starch glycogen, amylose, amylopectin, and mixtures thereof. Thebiodegradable hydrophilic or hydrophobic polymer may be a water-solublederivative of a poly-1,4-glucan, including hydrolyzed amylopectin,hydroxyalkyl derivatives of hydrolyzed amylopectin such as hydroxyethylstarch (HES), hydroxyethyl amylose, dialdehyde starch, and the like. Thepolyanhydride polymer may be branched or linear. Examples of polymerswhich are useful in the present invention include (in addition tohomopolymers and copolymers of poly(lactic acid) and/or poly(glycolicacid)) poly[bis(p-carboxyphenoxy)propane anhydride] (PCPP),poly[bis(p-carboxy)methane anhydride] (PCPM), polyanhydrides ofoligomerized unsaturated aliphatic acids, polyanhydride polymersprepared from amino acids which are modified to include an additionalcarboxylic acid, aromatic polyanhydride compositions, and co-polymers ofpolyanhydrides with other substances, such as fatty acid terminatedpolyanhydrides, e.g., polyanhydrides polymerized from monomers of dimersand/or trimers of unsaturated fatty acids or unsaturated aliphaticacids. Polyanhydrides may be prepared in accordance with the methods setforth in U.S. Pat. No. 4,757,128, incorporated herein by reference.Polyorthoester polymers may be prepared, e.g., as set forth in U.S. Pat.No. 4,070,347, incorporated herein by reference. Polyphosphoesters maybe prepared and used as set forth in U.S. Pat. Nos. 6,008,318,6,153,212, 5,952,451, 6,051,576, 6,103,255, 5,176,907 and 5,194,581,each of which is incorporated herein by reference.

Proteinaceous polymers may also be used. Proteinaceous polymers andtheir soluble derivatives include gelation biodegradable syntheticpolypeptides, elastin, alkylated collagen, alkylated elastin, and thelike. Biodegradable synthetic polypeptides includepoly-(N-hydroxyalkyl)-L-asparagine, poly-(N-hydroxyalkyl)-L-glutamine,copolymers of N-hydroxyalkyl-L-asparagine and N-hydroxyalkyl-L-glutaminewith other amino acids. Suggested amino acids include L-alanine,L-lysine, L-phenylalanine, L-valine, L-tyrosine, and the like.

In additional embodiments, the controlled release material, which ineffect acts as a carrier for a compound of the invention, alone or incombination with one or more biologically active agents as describedherein, can further include a bioadhesive polymer such as pectins(polygalacturonic acid), mucopolysaccharides (hyaluronic acid, mucin) ornon-toxic lectins or the polymer itself may be bioadhesive, e.g.,polyanhydride or polysaccharides such as chitosan.

In embodiments where the biodegradable polymer comprises a gel, one suchuseful polymer is a thermally gelling polymer, e.g., polyethylene oxide,polypropylene oxide (PEO-PPO) block copolymer such as Pluronic™ F127from BASF Wyandotte. In such cases, the local anesthetic formulation maybe injected via syringe as a free-flowing liquid, which gels rapidlyabove 30° C. (e.g., when injected into a patient). The gel system thenreleases a steady dose of a compound of the invention, alone or incombination with one or more biologically active agents as describedherein, at the site of administration.

Solid Dosage Forms for Oral Use

Formulations for oral use include tablets containing the activeingredient(s) in a mixture with non-toxic pharmaceutically acceptableexcipients. These excipients may be, for example, inert diluents orfillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystallinecellulose, starches including potato starch, calcium carbonate, sodiumchloride, lactose, calcium phosphate, calcium sulfate, or sodiumphosphate); granulating and disintegrating agents (e.g., cellulosederivatives including microcrystalline cellulose, starches includingpotato starch, croscarmellose sodium, alginates, or alginic acid);binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid,sodium alginate, gelatin, starch, pregelatinized starch,microcrystalline cellulose, magnesium aluminum silicate,carboxymethylcellulose sodium, methylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethyleneglycol); and lubricating agents, glidants, and antiadhesives (e.g.,magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenatedvegetable oils, or talc). Other pharmaceutically acceptable excipientscan be colorants, flavoring agents, plasticizers, humectants, bufferingagents, and the like.

Two or more compounds may be mixed together in a tablet, capsule, orother vehicle, or may be partitioned. In one example, the first compoundis contained on the inside of the tablet, and the second compound is onthe outside, such that a substantial portion of the second compound isreleased prior to the release of the first compound.

Formulations for oral use may also be provided as chewable tablets, oras hard gelatin capsules wherein the active ingredient is mixed with aninert solid diluent (e.g., potato starch, lactose, microcrystallinecellulose, calcium carbonate, calcium phosphate or kaolin), or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example, peanut oil, liquid paraffin, or olive oil.Powders, granulates, and pellets may be prepared using the ingredientsmentioned above under tablets and capsules in a conventional mannerusing, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.

Dissolution or diffusion controlled release can be achieved byappropriate coating of a tablet, capsule, pellet, or granulateformulation of compounds, or by incorporating the compound into anappropriate matrix. A controlled release coating may include one or moreof the coating substances mentioned above and/or, e.g., shellac,beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glycerylmonostearate, glyceryl distearate, glycerol palmitostearate,ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetatebutyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone,polyethylene, polymethacrylate, methylmethacrylate,2-hydroxymethacrylate, methacrylate hydrogels, 1,3 butylene glycol,ethylene glycol methacrylate, and/or polyethylene glycols. In acontrolled release matrix formulation, the matrix material may alsoinclude, e.g., hydrated methylcellulose, carnauba wax and stearylalcohol, carbopol 934, silicone, glyceryl tristearate, methylacrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/orhalogenated fluorocarbon.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally include aqueoussolutions, suitably flavored syrups, aqueous or oil suspensions, andflavored emulsions with edible oils such as cottonseed oil, sesame oil,coconut oil, or peanut oil, as well as elixirs and similarpharmaceutical vehicles.

Generally, when administered to a human, the oral dosage of any of thecompounds of the combination of the invention will depend on the natureof the compound, and can readily be determined by one skilled in theart. Typically, such dosage is normally about 0.001 mg to 2000 mg perday, desirably about 1 mg to 1000 mg per day, and more desirably about 5mg to 500 mg per day. Dosages up to 200 mg per day may be necessary.

Administration of each drug in a combination therapy, as describedherein, can, independently, be one to four times daily for one day toone year, and may even be for the life of the patient. Chronic,long-term administration will be indicated in many cases.

Topical Formulations

A composition of the invention, alone or in combination with one or moreof the biologically active agents described herein, can also be adaptedfor topical use with a topical vehicle containing from between 0.0001%and 25% (w/w) or more of active ingredient(s).

In a preferred combination, the active ingredients are preferably eachfrom between 0.0001% to 10% (w/w), more preferably from between 0.0005%to 4% (w/w) active agent. The cream can be applied one to four timesdaily, or as needed.

Performing the methods described herein, the topical vehicle containingthe composition of the invention, or a combination therapy containing acomposition of the invention is preferably applied to the site ofinflammation on the patient. For example, a cream may be applied to thehands of a patient suffering from arthritic fingers.

Formulations for Nasal and Inhalation Administration

The pharmaceutical compositions of the invention can be formulated fornasal or intranasal administration. Formulations suitable for nasaladministration, when the carrier is a solid, include a coarse powderhaving a particle size, for example, in the range of approximately 20 to500 microns which is administered by rapid inhalation through the nasalpassage. When the carrier is a liquid, for example, a nasal spray or asnasal drops, one or more of the formulations can be admixed in anaqueous or oily solution, and inhaled or sprayed into the nasal passage.

For administration by inhalation, the active ingredient can beconveniently delivered in the form of an aerosol spray presentation frompressurized packs or a nebulizer, with the use of a suitable propellant,e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol the dosage unit can be determined byproviding a valve to deliver a metered amount, Capsules and cartridgesof, for example, gelatin for use in an inhaler or insufflator can beformulated containing a powder mix of the compound and a suitable powderbase such as lactose or starch.

EXAMPLES

The following example is intended to illustrate the invention, and isnot intended to limit it.

Example 1 Treatment of Neurogenic Inflammation with IntravenousInjection of QX-314

FIG. 1 is a graph showing the effect of intravenous QX-314 (0.4 mg/kg)on the edema elicited by injection of complete Freund's adjuvant (CFA)in the rat hindpaw determined by measuring the total volume of thehindpaw by plethysmography. The degree of swelling produced by injectionof CFA is reduced by administration of QX-314 reflecting reduction inneurogenic edema resulting from the blockade of nociceptors by QX314.QX-314 by itself has no effect different from administration of saline.

Example 2 Entry of N-Methyl-Verapamil into Dorsal Root Ganglion NeuronsThrough Capsaicin-Activated TRPV1 Channels

N-methyl-verapamil, a charged derivative of the known calcium channelblocker verapamil and structurally related to D-890, can be loaded intodorsal root ganglion neurons through activation of TRPV1 channels bycapsaicin. The internally-loaded N-methyl-verapamil then produceslong-lasting inhibition of the voltage-dependent calcium channels in theneurons. Entry of the drug into the cell, and its blocking action,depends on applying the drug in the presence of capsaicin to activatethe TRPV1 channels present in the neuronal membrane.

As shown in FIG. 2, the inhibition of voltage-dependent calcium channelcurrent in a DRG neuron by N-methyl-verapamil applied in the presence ofcapsaicin to open TRPV1 channels. The traces show currents throughvoltage-activated calcium channels in a dissociated rat dorsal rootganglion neuron, recorded in whole-cell mode. Current was carried by 2mM Ba²⁺ on a background of 155 mM N-methyl-D-glucamine (to eliminate Nacurrent), with an internal CsCl-based solution. Calcium channels wereopened by a voltage step from −80 mV to −20 mV. When channels areopened, inward-going current is carried by Ba²⁺ ions flowing into thecell.

Each panel shows calcium channel currents before and 3 minutes afterexposure of the cell to either 1 μM capsaicin alone (top panel), 300 μMN-methyl-verapamil alone (middle panel), or 300 μM N-methyl-verapamilapplied in the presence of 1 μM capsaicin to open TRPV1 channels (bottompanel). Control experiments using either capsaicin alone orN-methyl-verapamil alone each produce weak, transient effects that arerapidly reversed when the agents are washed away. The combination,however, produces an inhibition of calcium channel currents thatpersists after washout of the agents, consistent with N-methyl-verapamilhaving entered through TRPV1 channels and remaining trapped inside thecells, blocking the calcium channels from the inside.

OTHER EMBODIMENTS

Various modifications and variations of the described method and systemof the invention will be apparent to those skilled in the art withoutdeparting from the scope and spirit of the invention. Although theinvention has been described in connection with specific desiredembodiments, it should be understood that the invention as claimedshould not be unduly limited to such specific embodiments. Indeed,various modifications of the described modes for carrying out theinvention that are obvious to those skilled in the fields of medicine,immunology, pharmacology, endocrinology, or related fields are intendedto be within the scope of the invention.

All publications mentioned in this specification are herein incorporatedby reference to the same extent as if each independent publication wasspecifically and individually incorporated by reference.

1. A method for treating neurogenic inflammation in a patient, saidmethod comprising administering to said patient a therapeuticallyeffective amount of a compound that is capable of (i) entering anociceptor through a channel-forming receptor present in said nociceptorwhen said receptor is activated and (ii) inhibiting a voltage-gated ionchannel present in said nociceptor, wherein said compound does notsubstantially inhibit said channel when applied to the extracellularface of said channel and when said receptor is not activated.
 2. Themethod of claim 1, wherein said compound inhibits voltage-gated sodiumchannels, or wherein said compound inhibits calcium channels.
 3. Themethod of claim 2, wherein said compound is QX-314, N-methyl-procaine,QX-222, N-octyl-guanidine, 9-aminoacridine, pancuronium, or another lowmolecular weight, charged molecule that inhibits voltage-gated sodiumchannels when present inside of said nociceptor.
 4. The method of claim1, wherein said compound is a quarternary amine derivative or othercharged derivative of a compound selected from the group consisting ofriluzole, mexilitine, phenyloin, carbamazepine, procaine, tocainide,prilocaine, articaine, bupivicaine, mepivicine, diisopyramide,bencyclane, quinidine, bretylium, lifarizine, lamotrigine, flunarizine,and fluspirilene; or wherein said compound is a quarternary aminederivative or other charged derivative of any of compounds (1)-(563). 5.(canceled)
 6. The method of claim 2, wherein said compound is selectedfrom D-890, CERM 11888, N-methyl-verapamil, N-methylgallopamil,N-methyl-devapamil, and dodecyltrimethylammonium; a quarternary aminederivative of verapamil, gallopamil, devapamil, diltiazem, fendiline,mibefradil, or farnesyl amine; a compound according to any of Formulas(XI), (XII), (XIII-A), (XIII-B), (XIII-C), and (XIV); and a quarternaryamine derivative or other charged derivative of any of compounds(45)-(563).
 7. (canceled)
 8. The method of claim 1, wherein saidchannel-forming receptor has been activated prior to said administeringof said compound.
 9. The method of claim 1, further comprisingadministering a second compound that activates said channel-formingreceptor.
 10. The method of claim 9, wherein said second compoundactivates a channel-forming receptor selected from TRPV1, P2X(2/3),TRPA1, and TRPM8.
 11. The method of claim 10, wherein said secondcompound is an activator of TRPV1 receptors, said activator selectedfrom capsaicin, a capsaicinoid, eugenol, arvanil(N-arachidonoylvanillamine), anandamide, 2-aminoethoxydiphenyl borate(2APB), AM404, resiniferatoxin, phorbol 12-phenylacetate 13-acetate20-homovanillate (PPAHV), olvanil (NE 19550), OLDA (N-oleoyldopamine),N-arachidonyldopamine (NADA), 6′-iodoresiniferatoxin (6′-IRTX), C18N-acylethanolamines, lipoxygenase derivatives such as12-hydroperoxyeicosatetraenoic acid, inhibitor cysteine knot (ICK)peptides (vanillotoxins), piperine, MSK195(N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-2-[4-(2-aminoethoxy)-3-methoxyphenyl]acetamide),JYL79(N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-N′-(4-hydroxy-3-methoxybenzyl)thiourea),hydroxy-alpha-sanshool, 2-aminoethoxydiphenyl borate, 10-shogaol,oleylgingerol, oleylshogaol, SU200(N-(4-tert-butylbenzyl)-N′-(4-hydroxy-3-methoxybenzyl)thiourea),articaine, benzocaine, bupivacaine, carbocaine, carticaine,chloroprocaine, cyclomethycaine, dibucaine (cinchocaine), dimethocaine(larocaine), etidocaine, hexylcaine, levobupivacaine, lidocaine,mepivacaine, meprylcaine (oracaine), metabutoxycaine, piperocaine,prilocaine, procaine (novacaine), proparacaine, propoxycaine, risocaine,ropivacaine, tetracaine (amethocaine), or trimecaine; or said secondcompound is an activator of TRPA1 receptors, said activator selectedfrom cinnamaldehyde, allyl-isothiocynanate, diallyl disulfide, icilin,cinnamon oil, wintergreen oil, clove oil, acrolein,hydroxy-alpha-sanshool, 2-aminoethoxydiphenyl borate, 4-hydroxynonenal,methyl p-hydroxybenzoate, mustard oil, and 3′-carbamoylbiphenyl-3-ylcyclohexylcarbamate (URB597), articaine, benzocaine, bupivacaine,carbocaine, carticaine, chloroprocaine, cyclomethycaine, dibucaine(cinchocaine), dimethocaine (larocaine), etidocaine, hexylcaine,levobupivacaine, lidocaine, mepivacaine, meprylcaine (oracaine),metabutoxycaine, piperocaine, prilocaine, procaine (novacaine),proparacaine, propoxycaine, risocaine, ropivacaine, tetracaine(amethocaine), or trimecaine; or said second compound is an activator ofP2X receptors, said activator selected from ATP, 2-methylthio-ATP, 2′and 3′-O-(4-benzoylbenzoyl)-ATP, and ATP5′-O-(3-thiotriphosphate); orsaid second compound is an activator of TRPM8 receptors, said activatorselected from menthol, iciclin, eucalyptol, linalool, geraniol, andhydroxycitronellal. 12.-14. (canceled)
 15. The method of claim 1,further comprising administering one or more acetaminophens, NSAIDs,glucocorticoids, narcotics, tricyclic antidepressants, amine transporterinhibitors, anticonvulsants, antiproliferative agents, or immunemodulators.
 16. The method of claim 1, wherein said method is used totreat asthma, conjunctivitis, sepsis, sinusisitis, cough, arthritis,colitis, contact dermatitis, eczema, gastritis, cystitis, urethritis,migraine headache, psoriasis, rhinitis, rosacea, sunburn, traumaticbrain injury, acute lung injury, chemical warfare agents, inhaled teargases, or inhaled pollutants.
 17. The method of claim 1, wherein saidadministering comprises intraarticular, surgical, intravenous,intramuscular, oral, rectal, cutaneous, subcutaneous, topical,transdermal, sublingual, nasal, vaginal, intraurethral, intravesicular,intrathecal, epidural, mucosal, aural, or ocular administration byinjection, inhalation, or direct contact.
 18. The method of claim 1,wherein said composition is formulated for controlled or sustainedrelease over time.
 19. A kit comprising: a) a compound that is capableof (i) entering a nociceptor through a channel-forming receptor presentin said nociceptor when said receptor is activated and (ii) inhibiting avoltage-gated ion channel present in said nociceptor, wherein saidcompound does not substantially inhibit said channel when applied to theextracellular face of said channel and when said receptor is notactivated; and b) instructions for administering said compound to apatient to treat neurogenic inflammation. 20.-31. (canceled)
 32. Acompound selected from the group consisting of: (a) a compound accordingto Formula (XI):

wherein each R^(11A), R^(11B), and R^(11C) is selected, independently,from H or C₁₋₄ alkyl, and X⁻ is any pharmaceutically acceptable anion;(b) a compound according to Formula (XII),

wherein each of R^(12A), R^(12B), R^(12C), and R^(12D) is,independently, selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₂₋₄ heteroalkyl, C₇₋₁₄ alkaryl, C₃₋₁₀ alkcycloalkyl, and C₃₋₁₀alkheterocyclyl; or R^(12A) and R^(12B) together complete a heterocyclicring having at least one nitrogen atom; n is an integer between 1-5;each of R^(12E) and R^(12F) is, independently, selected from H, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₇₋₁₄ alkaryl,C₃₋₁₀ alkcycloalkyl, or C₃₋₁₀ alkheterocyclyl; and X is anypharmaceutically acceptable anion;

wherein each R^(13A)-R^(13J) and R^(13O)-R^(13T) is selected,independently, from H, halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₂₋₄ heteroalkyl, C₇₋₁₄ alkaryl, C₃₋₁₀ alkcycloalkyl, and C₃₋₁₀alkheterocyclyl, OR^(13AA), NR^(13AB)R^(13AC), NR^(13AD)C(O)R^(13AE),S(O)R^(13AF), SO₂R^(13AG)R^(13AH), SO₂NR^(13AI)R^(13AJ), SO₃R^(13AK),CO₂R^(13AL), C(O)R^(13AM), and C(O)NR^(13AN)R^(13AO); each ofR^(13AA)-R^(13AO) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; each R^(13K), R^(13L),R^(13M), and R^(13N) is, independently, H or C₁₋₄ alkyl, or R^(13K) andR^(13L), or R^(13M) and R^(13N), combine to form C═O, or R^(13K) andR^(13M) combine to form C═C; R^(13Y) is H or C₁₋₄ alkyl; R^(13Z) andR^(13Z′) are, independently, selected from H, halogen, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₇₋₁₄ alkaryl, C₃₋₁₀alkcycloalkyl, and C₃₋₁₀ alkheterocyclyl; and X⁻ is any pharmaceuticallyacceptable anion; and (d) a compound having a structure according to

wherein n is an integer between 0-5; R^(14A) is heterocyclyl, each ofR^(14B), R^(14C), R^(14D), and R1^(4E) is, independently, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₇₋₁₄ alkaryl, C₃₋₁₀alkcycloalkyl, and C₃₋₁₀ alkheterocyclyl; and R^(14F) is selected fromH, halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl,C₇₋₁₄ alkaryl, C₃₋₁₀ alkcycloalkyl, and C₃₋₁₀ alkheterocyclyl, OR^(14G),NR^(14H)R^(14I), NR^(14J)C(O)R^(14K), S(O)R^(14L), S(O)₂R^(14M)R^(14N),SO₂NR^(14O)R^(14P), SO₃R^(14Q), CO₂R^(14R), C(O)R^(14S), andC(O)NR^(14T)R^(14V); and each of R^(14G)-R^(13AO) is, independently,selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄heteroalkyl.
 33. The compound of claim 32, wherein said compound is:

wherein X is a pharmaceutically acceptable anion. 34.-39. (canceled) 40.A pharmaceutical composition, comprising the compound of claim 32 and apharmaceutically acceptable excipient.
 41. A pharmaceutical composition,comprising a quarternary amine derivative or other charged derivative ofany of compounds (1)-(563).
 42. The pharmaceutical composition of claim40, wherein said composition is formulated for oral, nasal, orinhalation administration.
 43. The pharmaceutical composition of claim41, wherein said composition is formulation for oral, nasal, orinhalation administration.
 44. (canceled)